Total synthesis of the spirocyclic oxindole alkaloids corynoxine, corynoxine B, corynoxeine, and rhynchophylline

Article abstract of DOI:10.1002/ejoc.201201505

Racemic total syntheses of four spirocyclic oxindole alkaloids are reported. The general starting material was an N-2-butenylated 2-hydroxytryptamine, which underwent a base-mediated Mannich spirocyclisation with a functionalised aldehyde to generate the C-ring. The second key step was a Pd-catalysed cyclisation of an α-keto ester enolate (in the original aldehyde) onto an allylic carbonate (in the N-substituent) to form the D-ring. The stereoselectivities of the key steps were moderate, but the isomers were readily purified, so that the natural products could be conveniently prepared, three of them for the first time. Racemic total syntheses of the four title spirocyclic oxindole alkaloids are reported starting from 4-hydroxytryptamine. The key steps were a base-mediated Mannich spirocyclisation to form the C-ring, and a Pd-catalysed cyclisation of a keto ester enolate onto an allylic carbonate to form the D-ring. Thus, convenient syntheses of the alkaloids were achieved, for three of them for the first time. Copyright

Full text of DOI:10.1002/ejoc.201201505

FULL PAPER
DOI: 10.1002/ejoc.201201505
Total Synthesis of the Spirocyclic Oxindole Alkaloids Corynoxine, Corynoxine
B, Corynoxeine, and Rhynchophylline
Martin J. Wanner,[a] Steen Ingemann,[a] Jan H. van Maarseveen,[a] and Henk Hiemstra*[a]
Keywords: Total synthesis / Natural products / Alkaloids / Spiro compounds / Nitrogen heterocycles / Cyclization /
Homogeneous catalysis / Wittig reactions
Racemic total syntheses of four spirocyclic oxindole alkaloids
are reported. The general starting material was an N-2-
butenylated 2-hydroxytryptamine, which underwent a base-
mediated Mannich spirocyclisation with a functionalised al-
dehyde to generate the C-ring. The second key step was a
Pd-catalysed cyclisation of an α-keto ester enolate (in the
original aldehyde) onto an allylic carbonate (in the N-substi-
tuent) to form the D-ring. The stereoselectivities of the key
steps were moderate, but the isomers were readily purified,
so that the natural products could be conveniently prepared,
three of them for the first time.
The spirocyclic oxindole alkaloids 1–6 were already iso-
lated and characterised several decades ago.[2] In corynox-
ine (1) and corynoxine B (2), the two substituents in the D-
ring have a cis-relationship, and the compounds differ only
in the stereochemistry at the spiro carbon. Isoryncho-
phylline (3) and rynchophylline (4) are identical to the cory-
noxines except for the trans-orientation of the substituents
in the D-ring. Isocorynoxeine (5) and corynoxeine (6) have
a vinyl instead of an ethyl substituent. Although they are
stable under neutral conditions at room temp., all of these
compounds are stereochemically labile at the spiro centre at
higher temperatures in both acid and base, due to reversible
heterolytic cleavage of the C-3–C-7 bond, which is essen-
tially a retro-Mannich/Mannich process (see Scheme 1).[3]
Interestingly, in aqueous medium, 1, 3, and 5 are favoured
at pH 9 (ca. 3:1 mixture), while 2, 4, and 6 are preponderant
at pH 4 (also ca. 3:1). The preference for the latter group
of compounds in acidic conditions is ascribed to the pres-
ence of an intramolecular hydrogen-bond between the pro-
tonated N-4 and the oxindole carbonyl oxygen.[3]
Introduction
Several species of the genus Uncaria, flowering plants of
the Rubiaceae family, play a role in traditional Chinese and
Japanese medicine.[1] The derived crude drug “Gou-teng”
has been used, for example, for its antispasmodic, anti-
hypertensive, and sedative activities. The medicinal activity
is due to indole alkaloids present in several parts of the
plants, such as corynoxine, corynoxine B, isorhyncho-
phylline, rhynchophylline, isocorynoxeine, and corynoxeine
(Scheme 1). In this paper, we report efficient synthetic
routes to four of these oxindole alkaloids in racemic form.
Because of their biological activity, spirooxindole alk-
aloids have received considerable synthetic attention.[4,5] On
the other hand, research aimed at the synthesis of the title
alkaloids is scarce in the literature. Some 40 years ago, Ban,
Seto, and Oishi achieved the first total syntheses of the
rhynchophyllines in racemic form starting from 2-hydroxy-
tryptamine and ethyl formylacetate (Scheme 2).[6] Under
carefully controlled conditions, spirocyclisation resulted in
7, which was then N-functionalised and subjected to Dieck-
mann condensation and decarboxylation to give ketone 8
as a mixture of two spiro stereoisomers. Reaction of 8 with
methyl diethylphosphonoacetate in the presence of NaH,
followed by hydrogenation, formylation, and treatment with
diazomethane led to racemic 3 and 4, which were spectro-
scopically identical to the natural products.
Scheme 1. Spirocyclic indole alkaloids and their equilibration.
[a] Van ’t Hoff Institute for Molecular Sciences, University of
Amsterdam,
Science Park 904, 1098 XH Amsterdam, The Netherlands
Fax: +31-20-5255604
E-mail: h.hiemstra@uva.nl
Homepage: hims.uva.nl/soc
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201505.
1100
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1100–1106

Total Synthesis of Spirocyclic Oxindole Alkaloids
precursor was expected to be derived from Mannich-type
condensation of a 2-hydroxytryptamine derivative and an
aldehyde,[4] similar to the first step in the Ban synthesis
(Scheme 2).[5] With the knowledge that we would encounter
several stereochemical issues along our route, we embarked
on this approach, beginning with the synthesis of key start-
ing material 9.
Results and Discussion
For the selective synthesis of secondary amine 9, we
chose the Fukuyama procedure (Scheme 5).[10] Thus,
tryptamine was first converted into its p-nitrosulfonyl deriv-
ative, which, in turn, was alkylated with the appropriate all-
ylic bromide (i.e., 10) to give crystalline sulfonamide 11.
Bromide 10 was readily accessible from (E)-1,4-dibromo-2-
butene, as was recently reported by us.[9] At this stage, oxin-
dole 12 was generated in excellent yield by treatment of 11
with N-chlorosuccinimide in aqueous THF under carefully
controlled conditions. Removal of the sulfonyl group from
nitrogen gave the desired secondary allylic amine (i.e., 9) in
four steps from tryptamine, and 73% overall yield.
Scheme 2. Total synthesis of rhynchophyllines by Ban et al.
The only other synthetic work toward the rhynchophyl-
lines that has been described in the literature was based on
the oxidative transformation of corynanthe-type alkaloids
(Scheme 3). Thus, treatment of dihydrocorynantheine with
tert-butyl hypochlorite gave an unstable chloride, which, on
basic methanolysis and acidic hydrolysis, rearranged to give
an isomeric mixture of spiro oxindoles, thus concluding for-
mal syntheses of rhynchophyllines 3 and 4.[7] A stereoselec-
tive version of this reaction type was recently used to
achieve a formal total synthesis of isorhynchophylline in
enantiopure form.[8] Total syntheses of the corynoxines and
corynoxeines have not been described in the literature to
the best of our knowledge.
Scheme 3. Oxidative rearrangement to give spiro oxindole alk-
aloids.
We recently reported the total synthesis of corynanthe
alkaloids using a Tsuji–Trost allylic alkylation of an α-keto
ester to close the D-ring as the key step.[9] This methodo-
logy would directly lead to the formation of the D-ring of
spiro oxindole alkaloids 1–6 with the desired substituents
installed, including the vinyl substituent, so we set out to
investigate the use of this reaction for the synthesis of these
compounds. Our retrosynthetic approach is illustrated in
Scheme 4. Cyclisation by Pd-catalysed allylic alkylation can
provide access to any of the target alkaloids (i.e., 1–6). The
Scheme 5. Synthesis of spirocyclisation substrate 9.
As in our earlier work,[9] we wished to use aldehyde 13
as Mannich reaction partner, as in this compound, the key
ketone functionality is protected as a thioacetal.[11] How-
ever, all attempts to effect (enantioselective) spirocyclisation
between 9 and 13 under acidic conditions (using chiral biar-
ylphosphoric acids) failed, and no reaction was observed.
Much to our satisfaction, Mannich-type spirocyclisation
produced 14 in good yields in the presence of amine thio-
urea bifunctional catalysts (Scheme 6).[12] However, the ee
obtained for 14 was at most 14%, using Takamoto’s cata-
lyst.[13,14] More importantly, we were unable to deprotect
the dithioacetal to reveal the α-keto ester, which is essential
for the realisation of the Pd-catalysed cyclisation of the D-
ring.
We then decided to investigate the use of an unprotected
α-keto ester, which, however, led to different problems. First
of all, methyl ester aldehyde 15 appeared to be unstable
under the conditions of spirocyclisation. Therefore, tert-
butyl ester 16 was used,[15] but spirocyclisation did not take
place under conditions of amine thiourea catalysis
(Scheme 6). Instead, rapid enamine formation occurred
Scheme 4. Our retrosynthesis of spiro oxindole alkaloids.
Eur. J. Org. Chem. 2013, 1100–1106
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1101

M. J. Wanner, S. Ingemann, J. H. van Maarseveen, H. Hiemstra
FULL PAPER
onate. As the palladium source, we used the allylpalladium
chloride dimer, and, after a broad screening of ligands, 1,2-
bis(diphenylphosphanyl)ethane (dppe) appeared to be the
best phosphane ligand for the reaction. We then converted
the tert-butyl ester into its methyl ester (i.e., 21), not only
because the natural product is a methyl ester, but also be-
cause the tBu ester was fully unreactive towards the Wittig
reagent for introduction of the methoxymethylene group.
The transesterification reaction proceeded with only 57%
yield because of some epimerisation at C-15, even at 0 °C.
To our delight, methyl ester 21 reacted well in the Wittig
reaction to produce solely Z-alkene 22, which isomerised
cleanly to give the more stable E isomer (i.e., 23) under
the influence of trifluoroacetic acid mixed with 10% of the
anhydride to ensure anhydrous conditions. Finally, hydro-
genation gave racemic corynoxine (1), whose NMR spectro-
scopic data were identical to those of the reported natural
product.[1b]
Scheme 6. Different attempts to effect spirocyclisation.
leading to dienol 17, which appeared to be a stable com-
pound and useless for our purposes. We surmised that the
acidic thiourea facilitated dehydration and prevented depro-
tonation of the oxindole. Apparently, more basic conditions
were required to generate enough of the nucleophile to
rapidly trap the iminium intermediate. Much to our satis-
faction, in the presence of an excess of triethylamine, ester
16 did undergo the desired spirocyclisation to give a mix-
ture of 18 and 19 (Scheme 6). Unfortunately, chiral non-
racemic amines did not lead to any enantioselectivity.
The key Mannich condensation reaction between equi-
molar amounts of amine 9 and aldehyde 16 proceeded at
best in an anhydrous mixture (7:1 v/v) of acetonitrile and
triethylamine at room temp. After 20 min, an extra
0.5 equiv. aldehyde was added, and stirring was continued
for 2 h. Removal of the solvents under reduced pressure and
chromatography gave the two spiro diastereomers (i.e., 18
and 19) in 75% yield as a 1:2 mixture of isomers. Remarka-
bly, there was a considerable polarity difference between the
isomers so that separation on a flash column was easy, pro-
viding first minor isomer 18 in ca. 25% yield (90% pure,
contaminated with 17), and then major isomer 19 in 50%
isolated yield. The NMR spectra of the two spiro-oxindoles
provided convincing evidence for their structures, except for
the stereochemical assignments, which could be done at a
later stage after their conversion into the natural products
(vide infra).
Scheme 7. Total synthesis of racemic corynoxine (1).
The same series of reactions was applied to the major
spirocyclisation product 19 (Scheme 8). Palladium-cata-
lysed Tsuji–Trost allylic alkylation led to a 4:1 cis/trans mix-
ture of cyclisation products 24 and 25 in isolated yields of
56 and 14%, respectively, as crystalline solids. In a similar
way to that shown in Scheme 7, these tetracycles were con-
With spirooxindole isomers 18 and 19 in hand, we set
out to investigate their conversion into the target alkaloids.
When minor diastereomer 18 was subjected to ca. 3 equiv.
of a 1:1 molar mixture of the bases cesium carbonate and
diethylisopropylamine in the presence of 5mol-% of a palla-
dium catalyst, Tsuji–Trost cyclisation[16] occurred to give cis
product 20 in 63% yield after chromatographic purification
(Scheme 7). The trans product could not be isolated in a
detectable amount. The mixture of the two bases was im-
portant for a good yield to be achieved. We reasoned that
the soluble amine base picked up the proton from the sub-
Scheme 8. Total syntheses of racemic corynoxine B (2), corynoxeine
strate, and that this was then irreversibly trapped by carb- (6), and rhynchophylline (4).
1102
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1100–1106

Total Synthesis of Spirocyclic Oxindole Alkaloids
(160 mL), and the resulting solution was cooled in a –18 °C ice/
salt freezing mixture. N-Chlorosuccinimide (2.16 g, 16.2 mmol) was
added, and the mixture was stirred at –18 °C for 1 h, then in an ice
bath for 1 h and finally at room temp. for 1 h. Evaporation of the
solvent and chromatography of the residue on silica, using petro-
leum ether/EtOAc, 2:1 and 1:1, gave product 12 (7.90 g, 14.9 mmol,
verted into the target racemic natural products corynoxine
B (2),[1b] corynoxeine (6),[1a] and rhynchophylline (4)[1a] as
crystalline solids. The NMR spectroscopic data were iden-
tical to those reported in the literature for the natural prod-
ucts.
1
93%) as a solid, m.p. 140–142 °C. H NMR: δ = 8.81 (br. s, 1 H),
8.33 (d, J = 7.9 Hz, 2 H), 7.96 (d, J = 7.9 Hz, 2 H), 7.23–7.28 (m,
2 H), 7.06 (m, 1 H), 6.91 (d, J = 7.7 Hz, 1 H), 5.72–5.79 (m, 1 H),
5.56 (m, 1 H), 4.47 (d, J = 5.7 Hz, 2 H), 3.92 (d, J = 6.7 Hz, 2 H),
3.50 (m, 1 H), 3.24–3.41 (m, 2 H), 2.12–2.30 (m, 2 H), 1.47 (s, 9
H) ppm. 13C NMR: δ = 179.5, 153.0, 149.9, 145.4, 141.5, 129.4,
128.33, 128.3, 128.2, 127.7, 124.3, 123.9, 122.5, 109.9, 82.4, 65.8,
Conclusions
Efficient total syntheses are presented for the title alk-
aloids. From tryptamine, 9 steps were required to make
corynoxeine (2.5% overall yield), while 10 steps were
needed to synthesise corynoxine (3.3% overall), corynoxine
B (5.2%), and rhynchophylline (2.5%). The compounds
were obtained in racemic form, because a suitable catalyst
to achieve enantioselective spirocyclisation has yet to be de-
veloped. Likewise, adequate control of the diastereoselecti-
vities of the key steps, i.e., the spirocyclisation and the
Tsuji–Trost cyclisation, requires further research. On the
positive side, the isomeric products were readily separable,
and this enabled the total syntheses of a number of biolo-
gically interesting alkaloids for the first time.
49.4, 44.2, 43.2, 29.1, 27.6 ppm. IR (neat): ν = 1738, 1711, 1621,
˜
1531 cm–1. HRMS (FAB): calcd. for C25H30N3O8S [M + H]+
532.1753; found 532.1746.
Removal of the Nosyl Group from 12 To Give 9: A mixture of oxind-
ole 12 (6.39 g, 12.0 mmol), K2CO3 (4.98 g, 36.0 mmol), and thio-
phenol (3.72 mL, 36.0 mmol) in anhydrous DMSO (35 mL) was
stirred vigorously for 2.15 h. Extractive work-up with water and
EtOAc followed by chromatography on silica with, successively, pe-
troleum ether/EtOAc 1:1, EtOAc, and EtOAc/MeOH/Et3N 93:3:3,
and drying at 50 °C/0.02 mbar gave 9 (4.0 g, 11.56 mmol, 96%) as
1
a syrup. H NMR: δ = 7.83 (br. s, 1 H), 7.21–7.28 (m, 2 H), 7.05
(m, 1 H), 6.89 (m, 1 H), 5.77–5.83 (m, 1 H), 5.67–5.74 (m, 1 H),
4.53 (dd, J = 0.8, 6.0 Hz, 2 H), 3.58 (t, J = 6.1 Hz, 1 H), 3.22 (m,
2 H), 2.77 (m, 2 H), 2.16 (m, 2 H), 1.51 (s, 9 H) ppm. 13C NMR:
δ = 180.8, 153.1, 141.7, 133.7, 129.3, 127.7, 125.0, 123.9, 122.0,
Experimental Section
General Methods: All 1H and 13C NMR spectra (APT) were re-
corded with a Bruker Avance 400 spectrometer (1H at 400 and 13C
at 100 MHz) at room temp. in CDCl3. IR spectra were obtained
using a Bruker IFS 28 FT spectrophotometer. Analytical thin-layer
chromatography was performed using a Merck TLC plastic roll
500ϫ20 cm with silica gel 60 F254. Flash chromatography was per-
formed on Biosolve 60 Å (0.032–0.063 mm) silica gel. The chiral
columns used included Chiralcel® OD (Chiral Technologies
Europe, 0.46ϫ25 cm), Chiralpak® AD (Chiral Technologies
Europe, 0.46ϫ25 cm) and Chiralcel® OD-H (Chiral Technologies
Europe, 0.46ϫ25 cm) columns. Melting points were measured with
a Leitz-Wetzlar melting point microscope apparatus and are uncor-
rected. Mass spectra and accurate mass measurements were per-
formed using a JEOL JMS-SX/SX 102 A Tandem Mass Spectrom-
eter. Tetrahydrofuran (THF) was freshly distilled from sodium and
benzophenone. Commercially available reagents and solvents were
purchased from Biosolve, Sigma–Aldrich, Fluka, or Acros, and
were used as received.
109.7, 81.9, 66.9, 50.5, 45.5, 44.1, 30.3, 27.6 ppm. IR (neat): ν =
˜
3250, 1739, 1708, 1620 cm–1. HRMS (FAB): calcd. for C19H27N2O4
[M + H]+ 347.1971; found 347.1973.
tert-Butyl 2-Oxohex-5-enoate: Literature methods[15] were used, but
diethyl ether was replaced by dichloromethane to prevent precipi-
tation of the di-tert-butyl oxalate at –78 °C. A Grignard reagent
was prepared from 4-bromo-1-butene (9.7 g, 7.29 mL, 71.8 mmol)
and magnesium turnings (4.5 g, 188 mmol) in THF (75 mL). This
was added dropwise to a stirred solution of di-tert-butyl oxalate
(12.12 g, 60.0 mmol) in a mixture of THF (60 mL) and dichloro-
methane (100 mL) at –78 °C. The solution was stirred for 4 h at this
temperature, and then quenched with saturated NH4Cl solution.
Dilution with ether and extractive work-up gave the crude tert-
butyl ester (11.0 g, 59.8 mmol, quantitative), which was pure
1
enough for the next step. H NMR: δ = 5.82 (m, 1 H), 5.10 (d, J
= 17.0 Hz, 1 H), 5.05 (d, J = 10.1 Hz, 1 H), 2.91 (t, J = 7.3 Hz, 2
H), 2.49 (m, 2 H), 1.59 (s, 9 H) ppm. 13C NMR: δ = 194.4, 160.3,
Tryptamine Derivative 11:
A
mixture of p-nosyltryptamine[9]
136.1, 115.7, 83.9, 38.2, 27.8, 27.0 ppm. IR (neat): ν = 1719,
˜
(10.35 g, 30.0 mmol), bromide 10[9] (7.53 g, 30.0 mmol), and
K2CO3 (12.4 g, 90 mmol) in anhydrous DMSO (100 mL) was
stirred at room temp. for 4 h. The reaction was quenched with
water, NH4Cl solution (careful: CO2 evolution), and EtOAc. Dry-
ing (Na2SO4), evaporation of the solvent, and trituration of the
residue for 16 h with a mixture of EtOAc and petroleum ether gave
11 as a yellow solid (14.27 g, 27.7 mmol, 92.4%), m.p. 130–
131.5 °C. 1H NMR: δ = 8.18 (d, J = 8.2 Hz, 2 H), 8.06 (br. s, 1 H),
7.84 (d, J = 8.2 Hz, 2 H), 7.49 (d, J = 7.7 Hz, 1 H), 7.32 (d, J =
8.0 Hz, 1 H), 7.19 (m, 1 H), 7.12 (m, 1 H), 6.98 (br., 1 H) ppm.
13C NMR: δ = 153.0, 149.3, 145.5, 136.0, 128.7, 128.5, 127.8, 126.8,
123.8, 122.2, 121.9, 119.3, 118.2, 111.5, 111.2, 82.3, 65.9, 48.9, 47.5,
1642 cm–1. HRMS (FAB): calcd. for C10H17O3 [M + H]+ 185.1178;
found 185.1179.
Ozonolysis To Give tert-Butyl 2,5-Dioxopentanoate (16): Ozone was
bubbled through a solution of tert-butyl 2-oxohex-5-enoate (5.52 g,
30.0 mmol) in dichloromethane (100 mL) at –78 °C until a blue col-
our persisted. The excess ozone was destroyed with dimethyl sulf-
ide, and the ozonide was reduced by adding triphenylphosphane
(8.4 g, 32 mmol). After 2 h at room temperature, the solvent was
evaporated and the residue was purified on silica, with petroleum
ether/EtOAc, 3:2 as eluent, to give aldehyde 16 (3.65 g, 19.6 mmol,
65% over two steps) as a colourless oil. 1H NMR: δ = 8.83 (s, 1
H), 3.13 (t, J = 6.0 Hz, 2 H), 2.85 (t, J = 6.0 Hz, 2 H), 1.57 (s, 9
H) ppm. 13C NMR: δ = 199.4, 193.3, 159.7, 84.1, 37.0, 31.4,
27.5, 24.5 ppm. IR (neat): ν = 3414, 1738 cm–1. HRMS (FAB):
˜
calcd. for C25H30N3O7S [M + H]+ 516.1804; found 516.1804.
Oxidation of Indole 11 To Give Oxindole 12: Water (0.432 mL,
24 mmol) was added to a solution of 11 (8.24 g, 16.0 mmol) in THF
27.6 ppm. IR (neat): ν = 1721 cm–1. HRMS (FAB): calcd. for
˜
C9H15O4 [M + H]+ 187.0971; found 187.0974.
Eur. J. Org. Chem. 2013, 1100–1106
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1103

M. J. Wanner, S. Ingemann, J. H. van Maarseveen, H. Hiemstra
FULL PAPER
Methyl 2,5-Dioxopentanoate 15: Prepared by the same method as
16, i.e., Grignard reaction with dimethyl oxalate followed by ozon-
olysis, in a comparable yield.
and the residue obtained after extraction with aqueous NaHCO3
and EtOAc was purified by chromatography with EtOAc to give
21 (0.203 g, 0.575 mmol, 57%). 1H NMR: δ = 8.65 (br. s, 1 H),
7.40 (d, J = 7.4 Hz, 1 H), 7.22 (m, 1 H), 7.08 (m, 1 H), 6.94 (d, J
= 7.6 Hz, 1 H), 6.02 (dt, J = 17.0, 10.1 Hz, 1 H), 4.96–5.06 (m, 2
H), 3.83 (s, 3 H), 3.17–3.32 (m, 3 H), 3.07 (br. d, J = 6.1 Hz, 1 H),
2.50–2.59 (m, 3 H), 2.40–2.46 (m, 1 H), 2.0–2.10 (m, 1 H), 1.30–
1.45 (m, 1 H) ppm. 13C NMR: δ = 194.5, 181.2, 161.5, 140.1, 136.6,
133.4, 127.9, 124.6, 122.8, 117.1, 109.8, 70.6, 57.9, 56.9, 53.3, 52.8,
Dienamine Formation with Bifunctional Catalysts: From aldehyde
16 and amine 9 in various solvents, yellow dienamine 17 was the
1
major product. H NMR: δ = 8.10 (br. s, 1 H), 7.2–7.4 (m, 2 H),
7.12 (t, J = 7.8 Hz, 1 H), 6.93 (d, J = 7.9 Hz, 1 H), 6.30 (d, J =
13.5 Hz, 1 H), 6.19 (d, J = 11.3 Hz, 1 H), 5.7–5.8 (m, 2 H), 5.53
(s, 1 H), 5.25 (dd, J = 13.5, 11.3 Hz, 1 H), 4.55–4.65 (m, 2 H), 3.55
(t, J = 5.8 Hz, 1 H), 3.25 (m, 2 H), 2.3–2.4 (m, 1 H), 2.15–2.25 (m,
1 H), 1.56 (m, 9 H), 1.53 (m, 9 H) ppm.
48.5, 40.4, 34.7, 22.1 ppm. IR (neat): ν = 3559, 2804, 1724,
˜
1619 cm–1. HRMS (FAB): calcd. for C20H23N2O4 [M + H]+
355.1662; found 355.1658.
Spirocyclisation of 9 To Give 18 and 19: Aldehyde 16 (1.86 g,
10.0 mmol) was added to a stirred solution of amine 9 (3.46 g,
10.0 mmol) in a mixture of anhydrous acetonitrile (75 mL) and tri-
ethylamine (11 mL) at room temp. After 20 min, a second portion
of aldehyde 16 (1.73 g, 5.0 mmol) was added, and stirring was con-
tinued for 2 h. Evaporation of the solvents and chromatography
with petroleum ether/EtOAc 1:1, and then with petroleum ether/
EtOAc 2:3 containing 3% Et3N, gave minor isomer 18 (1.4 g, 90%
pure, 2.45 mmol, 25%) and major isomer 19 (2.58 g, 5.02 mmol,
50%), respectively. Total yield 75%. Data for 18: 1H NMR: δ =
8.36 (br. s, 1 H), 7.40 (d, J = 7.4 Hz, 1 H), 7.20–7.28 (m, 2 H), 6.93
(d, J = 7.8 Hz, 1 H), 5.8–6.0 (m, 2 H), 4.59 (d, J = 5.9 Hz, 2 H),
1.9–3.6 (m, 11 H), 1.51 (s, 9 H) ppm. 13C NMR: δ = 193.7, 182.2,
159.9, 153.1, 140.4, 132.7, 132.0, 129.6, 126.0, 125.0, 122.3, 109.9,
83.4, 81.8, 69.9, 66.8, 60.2, 54.7, 51.8, 35.9, 34.8, 34.4, 33.4, 27.7,
Wittig Reaction To Give 22: The phosphonium ylide was prepared
by stirring (methoxymethyl)triphenylphosphonium chloride
(0.616 g, 1.80 mmol) and potassium tert-butoxide (0.190 g,
1.70 mmol) for 5 min in THF (10 mL) at room temp. The orange-
red solution was cooled to –78 °C and added by syringe in one
portion to a solution of α-keto ester 21 (0.160 g, 0.45 mmol) in
THF (5 mL) cooled to –78 °C. The cooling bath was removed, and
the yellow solution was stirred for 2 h at room temp. Saturated
NH4Cl solution (10 mL), water (2 mL), and ethyl acetate (10 mL)
were added, and the resulting two-layer system was stirred for 44 h.
Extractive work-up and chromatography (petroleum ether/EtOAc,
1:1 and 1:2) gave 22 (0.115 g, 0.30 mmol, 67%). 1H NMR: δ = 8.50
(br. s, 1 H), 7.46 (d, J = 7.4 Hz, 1 H), 7.24 (m, 1 H), 7.10 (m, 1
H), 6.94 (d, J = 7.6 Hz, 1 H), 6.02 (dt, J = 17.0, 10.1 Hz, 1 H),
5.76 (s, 1 H), 5.10 (dd, J = 2.1, 10.3 Hz, 1 H), 4.96 (dd, J = 1.7,
17.5 Hz, 1 H), 3.71 (s, 3 H), 3.65 (s, 3 H), 3.28 (m, 1 H), 3.20 (dd,
J = 10.7, 1.7 Hz, 1 H), 2.75 (m, 1 H), 2.63 (m 1 H), 2.39–2.45 (m,
4 H), 2.05 (m, 1 H), 1.04 (m, 2 H) ppm. 13C NMR: δ = 181.3,
167.0, 156.4, 140.1, 137.3, 134.0, 127.6, 124.8, 122.6, 117.2, 110.2,
109.6, 72.3, 61.8, 57.7, 57.1, 53.3, 51.3, 42.2, 38.6, 35.1, 26.1 ppm.
28.0, 23.4 ppm. IR (neat): ν = 3280, 1736, 1725, 1618 cm–1. HRMS
˜
(FAB): calcd. for C28H39N2O7 [M + H]+ 515.2758; found 515.2755.
1
Data for 19: H NMR: δ = 7.95 (br. s, 1 H), 7.18–7.23 (m, 2 H),
7.05 (t, J = 7.5 Hz, 1 H), 6.90 (d, J = 7.7 Hz, 1 H), 5.99–6.04 (m,
1 H), 5.81–5.87 (m, 1 H), 4.60 (d, J = 6.1 Hz, 2 H), 3.56 (dd, J =
4.9, 13.7 Hz, 1 H), 3.34–3.39 (m, 1 H), 3.00 (dd, J = 7.8, 13.6 Hz,
1 H), 2.86 (dd, J = 3.9, 9.0 Hz, 1 H), 2.64–2.72 (m, 2 H), 2.32–2.45
(m, 2 H), 2.07–2.15 (m, 1 H), 1.88–2.01 (m, 2 H), 1.52 (s, 9 H),
1.47 (s, 9 H) ppm. 13C NMR: δ = 193.7, 181.2, 159.6, 153.0, 140.2,
134.8, 131.7, 127.8, 126.7, 122.6, 122.4, 109.9, 83.2, 81.8, 71.8, 66.7,
IR (neat): ν = 3273, 2798, 1704, 1644, 1618 cm–1. HRMS (FAB):
˜
calcd. for C22H27N2O4 [M + H]+ 383.1974; found 383.1970.
Double Bond Isomerisation To Give 23: A solution of 22 (0.087 g,
0.23 mmol) in a mixture of dichloromethane (1.5 mL), trifluoro-
acetic acid (TFA; 0.5 mL), and trifluoroacetic acid anhydride
(TFAA; 0.05 mL) was stirred under anhydrous conditions for 20 h
at room temp. The reaction was quenched by adding diethyl ether
(10 mL) and aqueous NaHCO3. Chromatography with petroleum
ether/EtOAc, 2:1, 1:1, and 1:2, gave E isomer 23 (0.067 g,
0.175 mmol, 76%) as a white foam. 1H NMR: δ = 8.48 (br. s, 1 H),
7.49 (d, J = 7.3 Hz, 1 H), 7.20 (m, 1 H), 7.18 (s, 1 H), 7.10 (m, 1
H), 6.91 (d, J = 7.7 Hz, 1 H), 6.23 (dt, J = 7.2, 17.1 Hz, 1 H), 4.87–
4.96 (m, 2 H), 3.58 (s, 3 H), 3.53 (s, 3 H), 3.26 (m, 1 H), 3.13 (dd,
J = 10.8, 2.0 Hz, 1 H), 2.83 (dt, J = 13.3, 3.7 Hz, 1 H), 2.39–2.55
(m, 4 H), 2.30 (br. d, 1 H), 2.05 (m, 1 H), 1.97 (m, 1 H), 1.05 (dt,
J = 2.9, 13.1 Hz, 1 H) ppm. 13C NMR: δ = 182.3, 168.9, 159.8,
140.3, 139.4, 134.4, 127.3, 124.7, 122.1, 114.1, 111.2, 109.6, 72.7,
56.6, 54.6, 52.5, 36.4, 35.0, 27.5, 27.4, 23.2 ppm. IR (neat): ν =
˜
3267, 1720, 1620 cm–1. HRMS (FAB): calcd. for C28H39N2O7 [M
+ H]+ 515.2758; found 515.2754.
Pd-Catalysed Cyclisation of 18 To Give 20: 1,2-Bis(diphenylphos-
phanyl)ethane (77.1 mg, 0.19 mmol) was added to a solution of
allylpalladium(II) chloride dimer (32.0 mg, 0.088 mmol, 5 mol-%)
in THF (5 mL) under argon. After stirring for 15 min, this solution
was added to a solution of ketone 18 (0.900 g, 1.75 mmol) in THF
(15 mL), and then Cs2CO3 (1.6 g, 5.0 mmol) and diisopropylethyla-
mine (0.87 mL, 5.0 mmol) were added. The mixture was stirred vig-
orously for 8 h, then it was quenched with aqueous NH4Cl, and
extracted with EtOAc. Chromatography with petroleum ether/
EtOAc 1:1, and with EtOAc containing 3% Et3N, gave 20 (0.441 g,
1
60.8, 58.6, 57.4, 53.8, 50.9, 44.0, 37.9, 34.7, 25.6 ppm. IR (neat): ν
˜
1.11 mmol, 63.4%) as a glass. H NMR: δ = 8.43 (br. s, 1 H), 7.40
=
3254, 2796, 1704, 1619 cm–1. HRMS (FAB): calcd. for
(d, J = 7.4 Hz, 1 H), 7.23 (m, 1 H), 7.08 (m, 1 H), 6.93 (d, J =
7.7 Hz, 1 H), 6.0 (dt, J = 17.1, 9.9 Hz, 1 H), 5.01–5.08 (m, 2 H),
3.30 (m, 1 H), 3.18 (m, 2 H), 3.03 (m, 1 H), 2.3–2.58 (m, 4 H), 1.9–
2.1 (m, 2 H), 1.52 (s, 9 H), 1.28 (m, 1 H) ppm. 13C NMR: δ =
195.8, 181.5, 160.7, 140.4, 136.6, 133.5, 127.7, 124.4, 122.6, 117.0,
110.0, 70.6, 57.9, 57.0, 53.3, 48.3, 40.4, 34.6, 28.3, 27.7, 22.0 ppm.
C22H27N2O4 [M + H]+ 383.1974; found 383.1974.
(؎)-Corynoxine (1): A solution of 23 (0.050 g, 0.13 mmol) in ethyl
acetate (3 mL) was stirred with 10% Pd/C (5 mg) under hydrogen
(1 atm) for 18 h. Filtration and evaporation of the solvent gave pure
(Ϯ)-corynoxine (1)[1a] (0.049 g, 0.127 mmol, 98%) as a crystalline
IR (neat): ν = 3286, 1718, 1619 cm–1. HRMS (FAB): calcd. for
˜
1
solid, m.p. 84–90 °C. H NMR: δ = 8.00 (br. s, 1 H), 7.47 (d, J =
C23H29N2O4 [M + H]+ 397.2127; found 397.2122.
7.3 Hz, 1 H), 7.25 (s, 1 H), 7.20 (m, 1 H), 7.07 (t, J = 7.5 Hz, 1 H),
6.88 (d, J = 7.7 Hz, 1 H), 3.61 (s, 3 H), 3.53 (s, 3 H), 3.20–3.26 (m,
2 H), 2.79 (dt, J = 13.3, 3.5 Hz, 1 H), 2.35–2.55 (m, 3 H), 2.17 (dd,
J = 11.1, 2.7 Hz, 1 H), 2.05 (m, 1 H), 1.84 (ddd, J = 13.1, 13.1,
13.4 Hz, 1 H), 1.65 (m, 1 H), 1.51 (m, 1 H), 1.12 (m, 1 H), 0.94
Transesterification of 20 To Give 21: A mixture of tert-butyl ester
20 (0.39 g, 0.98 mmol) and K2CO3 (10 mg) in absolute methanol
(50 mL) was stirred under anhydrous conditions at 0 °C for 8 h.
Acetic acid (50 μL) was added, then the solvent was evaporated,
1104
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1100–1106

Total Synthesis of Spirocyclic Oxindole Alkaloids
(dt, J = 13.0, 2.8 Hz, 1 H), 0.89 (t, J = 7.4 Hz, 3 H) ppm. 13C in THF (4 mL) at –78 °C. The cooling bath was removed, and the
NMR: δ = 182.4, 169.0, 160.1, 140.2, 134.6, 127.1, 124.7, 122.1,
yellow solution was stirred for 2 h at room temp. Saturated NH4Cl
111.6, 109.5, 72.9, 61.0, 57.4, 54.5, 53.8, 51.1, 40.1, 38.8, 34.7, 25.3, solution (10 mL), water (2 mL), and ethyl acetate (10 mL) were
19.2, 12.9 ppm. IR (neat): ν = 3250, 2796, 1707, 1620 cm–1. HRMS
added, and the resulting two-layer system was stirred for 44 h. Ex-
tractive work-up and chromatography (petroleum ether/EtOAc, 1:1
and 1:2) gave the Z and E isomers in a 4:1 ratio. The Z isomer was
difficult to separate from triphenylphosphane oxide, and so it was
used as such in the following step. The total yield was 0.090 g,
˜
(FAB): calcd. for C22H29N2O4 [M + H]+ 385.2127; found 385.2127.
Pd-Catalysed Cyclisation of 19 To Give 24 and 25: 1,2-Bis(diphenyl-
phosphanyl)ethane (88.0 mg, 0.24 mmol) was added to a solution
of allylpalladium(II) chloride dimer (36.6 mg, 0.10 mmol, 5 mol-%)
in THF (10 mL) under argon. After stirring for 15 min, this solu-
tion was added to a solution of ketone 19 (0.52 g, 1.0 mmol) in
THF (20 mL), and then Cs2CO3 (0.652 g, 2.0 mmol) and diiso-
propylethylamine (0.348 mL, 2.0 mmol) were added. The mixture
was stirred vigorously for 8 h, then it was quenched with aqueous
NH4Cl, and extracted with EtOAc. Chromatography with petro-
leum ether/EtOAc, 1:1 and with EtOAc containing 3% Et3N gave
24 (0.221 g, 0.558 mmol, 56%) and 25 (55.7 mg, 14%) both as sol-
ids. Data for cis isomer 24: M.p. 186–188 °C 1H NMR: δ = 8.77
(br. s, 1 H), 7.18–7.22 (m, 2 H), 7.04 (t, J = 7.5 Hz, 1 H), 6.94 (d,
J = 7.7 Hz, 1 H), 6.18 (dt, J = 10.0, 17.1 Hz, 1 H), 4.98–5.06 (m,
2 H), 3.38 (t, J = 8.1 Hz, 1 H), 3.26 (dd, J = 1.8, 10.9 Hz, 1 H),
3.0–3.15 (m, 2 H), 2.58 (m, 1 H), 2.45 (m, 2 H), 2.32, (dd, J = 11.6,
2.2 Hz, 1 H), 2.10 (m, 1 H), 1.90 (ddd, J = 12.2, 12.2, 12.7 Hz, 1
1
0.236 mmol, 66%. Data for Z isomer: H NMR: δ = 9.02 (s, 1 H),
7.17–7.22 (m, 2 H), 7.05 (dd, J = 0.8, 7.6 Hz, 1 H), 6.95 (d, J =
7.7 Hz, 1 H), 6.10 (dt, J = 10.0, 17.2 Hz, 1 H), 5.09 (dd, J = 2.1,
10.3 Hz, 1 H), 4.90 (dd, J = 1.8, 17.3 Hz, 1 H), 3.69 (s, 3 H), 3.61
(s, 3 H), 3.35 (m, 1 H), 3.24 (m, 1 H), 2.64 (m, 1 H), 2.32–2.60 (m,
3 H), 2.05 (m, 1 H), 1.59 (ddd, J = 11.9, 12.2, 11.8 Hz, 1 H), 1.07
(br. d, J = 11.8 Hz ) ppm. 13C NMR: δ = 181.9, 167.0, 157.0, 141.0,
137.1, 133.2, 1342.1, 132.0, 131.9, 128.5, 128.4, 127.9, 123.0, 122.6,
117.5, 109.7, 109.5, 75.6, 61.7, 60.3, 58.0, 56.2, 54.5, 51.2, 42.5,
39.1, 34.2, 25.6 ppm. IR (neat): ν = 3269, 2782, 1702, 1643,
˜
1620 cm–1. HRMS (FAB): calcd. for C22H27N2O4 [M + H]+
383.1970; found 383.1974. For data for the E isomer, see the prod-
uct of the following isomerisation experiment.
Double Bond Isomerisation To Give 26: A solution of the above
H), 1.49 (s, 9 H), 1.35 (m, 1 H) ppm. 13C NMR: δ = 195.4, 160.8, Z isomer (0.090 g, 0.236 mmol) in a mixture of dichloromethane
141.2, 136.7, 132.8, 128.0, 122.8, 122.4, 117.0, 109.7, 74.1, 58.3,
(1.5 mL), TFA (0.5 mL), and TFAA (0.05 mL) was stirred under
anhydrous conditions for 20 h at room temp. The reaction was
quenched by adding diethyl ether (10 mL) and aqueous NaHCO3.
Crystallisation from EtOAc and some petroleum ether 40/60 gave
E isomer 26 (0.0467 g, 0.122 mmol, 52%) as colourless crystals,
56.0, 54.5, 48.8, 40.7, 33.9, 27.7, 21.6 ppm. IR (neat): ν = 3250,
˜
2796, 1715, 1620 cm–1. HRMS (FAB): calcd. for C23H29N2O4 [M
+ H]+ 397.2127; found 397.2127. Data for trans-isomer 25: M.p.
181–185 °C. 1H NMR: δ = 7.75 (br. s, 1 H), 7.21–7.25 (m, 2 H),
7.06–7.10 (m, 1 H), 6.69 (m, 1 H), 5.62 (m, 1 H), 5.09 (d, J = m.p. 192–196 °C. 1H NMR: δ = 8.86 (br. s, 1 H), 7.22 (s, 1 H),
17.2 Hz, 1 H), 5.01 (dd, J = 1.3, 10.3 Hz, 1 H), 3.45 (m, 1 H), 3.30 7.17–7.23 (m, 2 H), 7.04 (m, 1 H), 6.92 (d, J = 7.7 Hz, 1 H), 6.36
(dd, J = 4.1, 11.1 Hz, 1 H), 3.03 (dt, J = 3.6, 11.8 Hz, 1 H), 2.73 (dt, J = 9.9, 17.1 Hz, 1 H), 4.94 (dd, J = 2.4, 10.1 Hz, 1 H), 4.86
(m, 1 H), 2.50–2.55 (m, 2 H), 2.34 (dd, J = 2.4, 11.3 Hz, 1 H), 2.10
(dd, J = 2.2, 17.1 Hz, 1 H), 3.61 (s, 3 H), 3.55 (s, 3 H), 3.35 (m, 1
(m, 1 H), 1.98 (t, J = 11.0 Hz, 1 H), 1.74 (ddd, J = 12.0, 12.0, H), 3.23 (d, J = 8.8 Hz, 1 H), 2.72 (dt, J = 3.4, 13.1 Hz, 1 H), 2.29–
11.7 Hz, 1 H), 1.48 (s, 9 H), 0.89 (m, 1 H) ppm. 13C NMR: δ =
196.6, 181.4, 160.7, 141.0, 137.1, 133.0, 128.2, 122.9, 122.6, 117.3,
109.9, 83.9, 73.5, 57.8, 55.8, 54.5, 48.5, 42.7, 34.5, 27.7, 27.4 ppm.
2.60 (m, 6 H), 2.05 (m, 1 H), 1.15 (br. d, J = 12.6 Hz, 1 H) ppm.
13C NMR: δ = 181.8, 169.0, 160.1, 141.2, 139.2, 133.4, 127.8, 123.0,
122.3, 114.3, 110.9, 109.4, 76.2, 61.2, 58.9, 56.4, 54.9, 51.1, 44.2,
IR (neat): ν = 3245, 2791, 1716, 1620 cm–1. HRMS (FAB): calcd.
39.1, 34.0, 25.1 ppm. IR (neat): ν = 3257, 2782, 1704, 1645,
˜
˜
for C23H29N2O4 [M + H]+ 397.2127; found 397.2122.
1620 cm–1. HRMS (FAB): calcd. for C22H27N2O4 [M + H]+
383.1970; found 383.1974.
Transesterification of 24 To Give the Methyl Ester: A mixture of
tert-butyl ester 24 (0.198 g, 0.98 mmol) and K2CO3 (5 mg) in abso-
lute methanol (25 mL) was stirred under anhydrous conditions for
6 h at 0 °C. Acetic acid (30 μL) was added, the solvent was evapo-
rated, and the residue obtained after extraction with aqueous
NaHCO3 and ethyl acetate was purified by chromatography with
(؎)-Corynoxine B (2): A solution of 26 (0.020 g, 0.052 mmol) in
ethyl acetate (2 mL) was stirred with Pd/C (10%; 4 mg) under H2
(1 atm) for 18 h. Filtration and evaporation of the solvent gave pure
corynoxine B (2)[1a] (0.020 g, 0.052 mmol, quantitative) as a crystal-
line solid, m.p. 184–188 °C. 1H NMR: δ = 8.29 (br. s, 1 H), 7.32
(s, 1 H), 7.17–7.22 (m, 2 H), 7.04 (m, 1 H), 6.87 (d, J = 7.7 Hz, 1
petroleum ether/EtOAc 1:1 to give the methyl ester of 24 (0.132 g,
1
0.372 mmol, 75%). H NMR: δ = 7.62 (br. s, 1 H), 7.20–7.24 (m, H), 3.64 (s, 3 H), 3.63 (s, 3 H), 3.35 (m, 1 H), 3.30 (dd, J = 1.9,
2 H), 7.06 (m, 1 H), 6.88 (m, 1 H), 6.18 (dt, J = 10.1, 17.2 Hz, 1
11.1 Hz, 1 H), 2.66 (dt, J = 2.4, 13.0 Hz, 1 H), 2.30–2.60 (m, 3 H),
H), 4.96 (dd, J = 1.3, 17.2 Hz, 2 H), 3.84 (s, 3 H), 3.36 (m, 1 H), 2.23 (m, 1 H), 2.05 (m, 2 H), 1.80 (m, 1 H), 1.51 (m, 1 H), 1.20 (m
3.25 (dd, J = 2.3, 11.0 Hz, 1 H), 3.15 (dt, J = 3.7, 12.4 Hz, 1 H), 1 H), 1.08 (br. d, J = 12.4 Hz, 1 H), 0.89 (t, J = 7.5 Hz, 3 H) ppm.
3.07 (m, 1 H), 2.40–2.60 (m, 3 H), 2.33 (dd, J = 2.5, 11.7 Hz, 1 H),
2.09 (m, 1 H), 1.91 (ddd, J = 12.1, 12.2, 12.8 Hz, 1 H), 1.36 (m, 1
H) ppm. 13C NMR: δ = 194.3, 181.3, 161.2, 141.2, 136.4, 132.6,
127.9, 122.6, 122.3, 116.8, 109.5, 73.5, 57.8, 56.0, 54.3, 52.6, 48.7,
13C NMR: δ = 181.5, 169.1, 160.4, 141.0, 133.7, 127.7, 123.1, 122.3,
111.4, 109.2, 76.7, 61.5, 56.3, 55.0, 54.9, 51.2, 40.3, 40.1, 34.0, 24.9,
19.1, 13.3 ppm. IR (neat): ν = 3258, 2782, 1704, 1645, 1620 cm–1.
˜
HRMS (FAB): calcd. for C22H29N2O4 [M + H]+ 385.2127; found
385.2127.
40.4, 33.6, 21.4 ppm. IR (neat): ν = 3352, 2786, 1720, 1620 cm–1.
˜
HRMS (FAB): calcd. for C20H23N2O4 [M + H]+ 355.1658; found
355.1662.
Transesterification of 25: A mixture of tert-butyl ester 25 (0.080 g,
0.20 mmol) and K2CO3 (2 mg) in absolute methanol (10 mL) was
stirred under anhydrous conditions for 6 h at 0 °C. Acetic acid
(20 mL) was added, the solvent was evaporated, and the methyl
ester obtained after extraction with aqueous NaHCO3 and ethyl
acetate was pure enough for the next step (0.057 g, 0.16 mmol,
Wittig Reaction with the Methyl Ester Analogue of 24: The phos-
phonium ylide was prepared by stirring (methoxymethyl)triphenyl-
phosphonium chloride (0.491 g, 1.44 mmol) and potassium tert-
butoxide (0.157 g, 1.40 mmol) for 5 min in THF (8 mL) at room
temp. The orange-red solution was cooled to –78 °C and added in
one portion to a solution of the α-keto ester (0.127 g, 0.359 mmol)
1
90%). Data for the methyl ester of 25: H NMR: δ = 8.61 (br. s, 1
H), 7.22–7.25 (m, 2 H), 7.09 (m, 1 H), 6.94 (m, 1 H), 5.56 (ddd, J
Eur. J. Org. Chem. 2013, 1100–1106
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1105

M. J. Wanner, S. Ingemann, J. H. van Maarseveen, H. Hiemstra
109.4, 99.9, 75.3, 61.6, 58.2, 56.1, 55.0, 51.3, 37.8, 34.8, 29.6, 28.9,
FULL PAPER
= 9.4, 10.3, 17.3 Hz, 1 H), 5.07 (d, J = 17.3 Hz, 1 H), 5.01 (dd, J
= 1.3, 10.3 Hz, 1 H), 3.78 (s, 3 H), 3.45 (m, 1 H), 3.33 (dd, J = 4.2,
11.1 Hz, 1 H), 3.14 (dt, J = 3.8, 11.7 Hz, 1 H), 2.75–2.83 (m, 1 H),
2.49–2.61 (m, 2 H), 2.37 (dd, J = 2.4, 11.2 Hz, 1 H), 2.05–2.15 (m,
1 H), 2.00 (t, J = 11.1 Hz, 1 H), 1.68 (ddd, J = 11.8, 11.7, 12.0 Hz,
1 H), 1.50–1.60 (m, 1 H) ppm. 13C NMR: δ = 195.2, 181.7, 161.4,
141.1, 136.9, 132.9, 128.1, 122.8, 122.5, 117.3, 110.1, 73.2, 57.5,
24.1, 11.3 ppm. IR (neat): ν = 3214, 2786, 1705, 1636, 1621 cm–1.
˜
HRMS (FAB): calcd. for C22H29N2O4 [M + H]+ 385.2127; found
385.2127.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H and 13C NMR spectra for all key intermedi-
ates and final products.
55.7, 54.4, 52.8, 48.3, 42.2, 34.6, 27.4 ppm. IR (neat): ν = 3248,
˜
2793, 1726, 1620 cm–1. HRMS (FAB): calcd. for C20H23N2O4 [M
+ H]+ 355.1662; found 355.1658.
[1] See, for example: a) I. Sakakibara, H. Takahashi, S. Terabaya-
shi, M. Yuzurihara, M. Kubo, A. Ishige, M. Higuchi, Y. Kom-
atsu, M. Okada, M. Maruno, C. Biqiang, H. Jiang, Phytomed-
icine 1998, 5, 83–86; b) I. Sakakibara, S. Terabayashi, M.
Kubo, M. Higuchi, Y. Komatsu, M. Okada, K. Taki, J. Kamei,
Phytomedicine 1999, 6, 163–168; c) Y. Shimada, H. Goto, T.
Itoh, I. Sakakibara, M. Kubo, H. Sasaki, K. Terasawa, J.
Pharm. Pharmacol. 1999, 51, 715–722; d) T.-J. Kim, J.-H. Lee,
J.-J. Lee, J.-Y. Yu, B.-Y. Hwang, S.-K. Ye, L. Shujuan, L. Gao,
M.-Y. Pyo, Y.-P. Yun, Biol. Pharm. Bull. 2008, 31, 2073–2078.
[2] J. S. Bindra, in: The Alkaloids (Ed.: R. H. F. Manske), Aca-
demic Press, New York, 1973, pp. 84–121.
[3] a) G. Laus, J. Chem. Soc. Perkin Trans. 2 1998, 315–317; b) for
a lucid discussion of the equilibrium, see: A. Lerchner, E. M.
Carreira, Chem. Eur. J. 2006, 12, 8209–8219.
[4] For reviews, see: a) C. Marti, E. Carreira, Eur. J. Org. Chem.
2003, 2209–2219; b) C. V. Galliford, K. A. Scheidt, Angew.
Chem. 2007, 119, 8902–8912; Angew. Chem. Int. Ed. 2007, 46,
8748–8758; c) R. Dalpozzo, G. Bartoli, G. Bencivenni, Chem.
Soc. Rev. 2012, 41, 7247–7290.
Wittig Reaction with the Methyl Ester of 25: The phosphonium
ylide was prepared by stirring (methoxymethyl)triphenylphosphon-
ium chloride (0.274 g, 0.80 mmol) and potassium tert-butoxide
(0.084 g, 0.75 mmol) for 5 min in THF (3 mL) at room temp. The
orange-red solution was cooled to –78 °C and added in one portion
to a solution of the α-keto ester (0.063 g, 0.18 mmol) in THF
(3 mL) at –78 °C. The cooling bath was removed, and the yellow
solution was stirred for 2 h at room temp. Saturated NH4Cl solu-
tion (10 mL), water (2 mL), and ethyl acetate (10 mL) were added,
and the resulting two-layer system was stirred for 44 h. Extractive
work-up and chromatography (EtOAc) gave a mixture of Z and E
isomers, together with triphenylphosphane oxide and phosphon-
ium salts. This mixture was isomerised with TFA in the following
step.
Double Bond Isomerisation To Give (؎)-Corynoxeine (6): A solution
of the crude E/Z mixture (0.18 mmol) from the previous section in
a mixture of dichloromethane (1.5 mL), TFA (0.5 mL), and TFAA
(0.05 mL) was stirred under anhydrous conditions for 20 h at room
temp. The reaction was quenched by adding diethyl ether (10 mL)
and aqueous NaHCO3. The product was extracted into dilute HCl
solution, and this mixture and extracted with ethyl acetate to re-
move triphenylphosphane oxide and phosphonium salts. Basifica-
tion of the aqueous phase with aqueous NaHCO3 and chromatog-
raphy with EtOAc gave (Ϯ)-corynoxeine (6)[1b] (0.038 g, 0.10 mmol,
55% over two steps) as a solid, m.p. 204–206 °C. 1H NMR: δ =
7.95 (br. s, 1 H), 7.25 (s, 1 H), 7.18–7.23 (m, 2 H), 7.06 (m, 1 H),
6.87 (d, J = 7.7 Hz, 1 H), 5.53 (m, 1 H), 4.91–5.0 (m, 2 H), 3.75
(s, 3 H), 3.63 (s, 3 H), 3.40 (m, 1 H), 3.29 (dd, J = 4.1, 10.8 Hz, 1
H), 2.99–3.08 (m, 1 H), 2.60–2.40 (m, 3 H), 2.32 (dd, J = 2.4,
11.3 Hz, 1 H), 1.98–2.08 (m, 2 H), 1.91 (t, J = 10.9 Hz, 1 H), 1.25
(m, 1 H) ppm. 13C NMR: δ = 181.6, 159.7, 141.0, 139.4, 133.7,
127.8, 123.1, 122.4, 115.4, 109.4, 100.0, 75.0, 61.5, 58.8, 56.0, 54.8,
[5] For a recent approach, see: X. Wu, Q. Liu, H. Fang, J. Chen,
W. Cao, G. Zhao, Chem. Eur. J. 2012, 18, 12196–12201, and
references cited therein.
[6] Y. Ban, M. Seto, T. Oishi, Chem. Pharm. Bull. 1975, 23, 2605–
2613.
[7] A. Deiters, M. Pettersson, S. F. Martin, J. Org. Chem. 2006,
71, 6547–6561.
[8] K. Nagata, H. Ishikawa, A. Tanaka, M. Miyazaki, T. Kanem-
itsu, T. Itoh, Heterocycles 2010, 81, 1791–1798.
[9] M. J. Wanner, E. Claveau, J. H. van Maarseveen, H. Hiemstra,
Chem. Eur. J. 2011, 17, 13680–13683.
[10] T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995,
36, 6373–6374.
[11] a) G. Massiot, T. Mulamba, J. Lévy, Bull. Soc. Chim. Fr. 1982,
241–248; b) J. Gonzalez, F. Sanchez, T. Torres, Synthesis 1983,
911–913.
[12] For a review, see: W.-Y. Siau, J. Wang, Catal. Sci. Technol.
2011, 1, 1298–1310.
51.2, 42.0, 34.8, 28.8 ppm. IR (neat): ν = 3221, 2785, 1705, 1638,
˜
[13] T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003,
1621 cm–1. HRMS (FAB): calcd. for C22H27N2O4 [M + H]+
383.1971; found 383.1974.
125, 12672–12673.
[14] For reviews on asymmetric approaches, see: a) B. M. Trost,
M. K. Brennan, Synthesis 2009, 3003–3025; b) F. Zhou, Y. Liu,
J. Zhou, Adv. Synth. Catal. 2010, 352, 1381–1407.
[15] Ester 16 was made by ozonolysis of the corresponding alkene,
which was known: a) A. Nakamura, S. Lectard, D. Hashizume,
Y. Hamashima, M. Sodeoka, J. Am. Chem. Soc. 2010, 132,
4036–4037; b) J. A. Macritchie, A. Silcock, C. L. Willis, Tetra-
hedron: Asymmetry 1997, 8, 3895–3902.
Hydrogenation of 6 To Give (؎)-Rhynchophylline (4): A solution of
6 (0.021 g, 0.055 mmol) in a mixture of ethyl acetate (4 mL) and
methanol (1 mL) was stirred with Pd/C (10%; 4 mg) under hydro-
gen (1 atm) for 18 h. Filtration and evaporation of the solvent gave
pure rhynchophylline (4)[1a] (0.0205 g, 0.053 mmol, 97%) as a crys-
talline solid, m.p. 194–198 °C. H NMR: several broad signals[9,17]
1
δ = 8.90 and 8.81 (br. s, 1 H), 7.27 (s, 1 H), 7.16–7.23 (m, 2 H),
7.04 (m, 1 H), 6.92 (d, J = 7.5 Hz, 1 H), 3.72 (s, 3 H), 3.62 (s, 3
H), 2.4–2.6 (m, 2 H), 2.20–2.35 (m, 2 H), 1.9–2.1 (m, 2 H), 1.67 (t,
J = 10.4 Hz, 1 H), 0.9–1.5 (m, 4 H), 0.82 (t, J = 7.3 Hz, 3 H) ppm.
13C NMR: δ = 181.8, 159.7, 141.0, 133.8, 127.7, 123.1, 122.4, 111.8,
[16] B. M. Trost, M. L. Crawley, Chem. Rev. 2003, 103, 2921–2944.
[17] D. Staerk, P.-O. Norrby, J. W. Jaroszevski, J. Org. Chem. 2001,
66, 2217–2221.
Received: November 9, 2012
Published Online: January 7, 2013
1106
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 1100–1106