Studies toward the Total Synthesis of the Oxindole Alkaloid Gelsedine: An Efficient Allene-Terminated N-Acyliminium Ion Cyclization

Article abstract of DOI:10.1021/jo971510n

This paper reports the synthesis of the advanced intermediate 26 in a projected synthesis of enantiopure ent-gelsedine (5). The route starts from (S)-malic acid and features the creation of four new stereocenters with complete control of stereochemistry. The key step is a novel allene-terminated N-acyliminium ion cyclization that leads to the required 7-azabicyclo[4.2.1]nonane-4,8-dione skeleton. Additional functionalities including the C-8 ethyl and the C-9 hydroxymethyl are introduced in an efficient manner.

Full text of DOI:10.1021/jo971510n

8862
J . Org. Chem. 1997, 62, 8862-8867
Stu d ies tow a r d th e Tota l Syn th esis of th e Oxin d ole Alk a loid
Gelsed in e: An Efficien t Allen e-Ter m in a ted N-Acylim in iu m Ion
Cycliza tion
Winfred G. Beyersbergen van Henegouwen and Henk Hiemstra*
Laboratory of Organic Chemistry, Amsterdam Institute of Molecular Studies, University of Amsterdam,
Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands
Received August 13, 1997X
This paper reports the synthesis of the advanced intermediate 26 in a projected synthesis of
enantiopure ent-gelsedine (5). The route starts from (S)-malic acid and features the creation of
four new stereocenters with complete control of stereochemistry. The key step is a novel allene-
terminated N-acyliminium ion cyclization that leads to the required 7-azabicyclo[4.2.1]nonane-
4,8-dione skeleton. Additional functionalities including the C-8 ethyl and the C-9 hydroxymethyl
are introduced in an efficient manner.
In tr od u ction
in 1962 on the basis of a spectroscopic comparison with
its 11-methoxy analogue gelsemicine (4). The structure
of 4 was already determined in 1961 through X-ray
crystallography by Przybylska and Marion.8 In 1994, the
first formal total synthesis of gelsedine starting from
koumidine, an intermediate in Magnus’ koumine syn-
thesis,2 was accomplished by Sakai et al.9 Other studies
aimed at a more direct total synthesis of gelsedine have
been reported by three groups,10 but a successful total
synthesis has not yet appeared.
Our retrosynthetic analysis to gelsedine starting from
malic acid is shown in Scheme 1. By using the inexpen-
sive (S)-enantiomer as starting material, we realized that
we would eventually arrive at ent-gelsedine (5), but this
was preferred over a racemic synthesis. In analogy with
our strategy to gelsemine,3 we envisaged the closure of
the tetrahydropyran ring via electrophile-induced etheri-
fication of 6 as a key step to complete the construction of
the skeleton. Heck cyclization of the suitably protected
amide 7 should lead to the oxindole 6.3,11 It is known
that the stereochemistry of the Heck cyclization can be
influenced by the choice of the catalyst.3,12 Regioselective
enolate formation from 8, followed by its trapping as an
enol triflate and Pd-catalyzed aminocarbonylation, should
lead to anilide 7.13 The conversion of 9 to 8 depends on
the stereoselective introduction of a two-carbon and a
one-carbon fragment on C-8 and C-9, respectively. Treat-
ment of 10 with acid will generate an N-acyliminium ion,
The three species of the plant genus Gelsemium
(Loganiaceae) are a rich source of indole alkaloids with
remarkably complex and diverse structures.1 The most
salient examples are the skeletons present in the parent
compounds koumine (1), gelsemine (2), and gelsedine (3).
Success in the area of total synthesis of these structures
is only of relatively recent date, when Magnus and co-
workers reported the first total synthesis of koumine in
1989.2 More recently, a number of total syntheses of
gelsemine were published by our group3 and others.4 This
paper deals with a portion of our recent work toward the
total synthesis of gelsedine. Our studies are motivated
by the challenging molecular architecture of the Gelsemi-
um alkaloids and by the interesting biological activity
that some of these natural products display. In fact,
extracts from Gelsemium species have a rich medicinal
history, particularly in China.1
(4) (a) Dutton, J . K.; Steel, R. W.; Tasker, A. S.; Popsavin, V.;
J ohnson, A. P. J . Chem. Soc., Chem. Commun. 1994, 765. (b) Kuzmich,
D.; Wu, S. C.; Ha, D.-C.; Lee, C.-S.; Ramesh, S.; Atarashi, S.; Choi,
J .-K.; Hart, D. J . J . Am. Chem. Soc. 1994, 116, 6943. (c) Fukuyama,
T.; Gang, L. J . Am. Chem. Soc. 1996, 118, 7426. (d) Atarashi, S.; Choi,
J .-K.; Ha, D.-C.; Hart, D. J .; Kuzmich, D.; Lee, C.-S.; Ramesh, S.; Wu,
S. C. J . Am. Chem. Soc. 1997, 119, 6226.
(5) Schwarz, H.; Marion, L. Can. J . Chem. 1953, 31, 958.
(6) Yang, Y.-S.; Chen, Y.-W. Acta Pharm. Sin. 1983, 18, 104
(7) Wenkert, E.; Orr, J . C.; Garratt, S.; Hansen, J . H.; Wickberg,
B.; Leicht, C. L. J . Org. Chem. 1962, 27, 4123.
(8) Przybylska, M.; Marion, L. Can. J . Chem. 1961, 39, 2124.
(9) Takayama, H.; Tominaga, Y.; Kitajama, M.; Aimi, N.; Sakai, S.
J . Org. Chem. 1994, 59, 4381.
Gelsedine (3) was isolated from Carolina jasmine
(Gelsemium sempervirens) in 1953 by Schwarz and
Marion5 and was later found to occur also in G. elegans.6
Its structure was elucidated by Wenkert and co-workers7
(10) (a) Baldwin, S. W.; Doll, R. J . Tetrahedron Lett. 1979, 35, 3275.
(b) Kende, A. S., Luzzio, M. J ., Mendoza, J . S. J . Org. Chem. 1990, 55,
918. (c) Hamer, N. K. J . Chem. Soc., Chem. Commun. 1990, 102.
(11) Abelman, M. M.; Oh, T.; Overman, L. E. J . Org. Chem. 1987,
52, 4130.
(12) Madin, A.; Overman, L. E. Tetrahedron Lett. 1992, 33, 4859.
(13) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26,
1109.
X Abstract published in Advance ACS Abstracts, November 15, 1997.
(1) For reviews on Gelsemium alkaloids, see: (a) Liu, Z.-J .; Lu, R.-
R. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1988;
Vol. 33, p 83. (b) Saxton, J . E. In The Alkaloids; Manske, R. H. F.,
Ed.; Academic Press: New York, 1965; Vol. 8, p 93.
(2) Magnus, P.; Mugrage, B.; DeLuca, M. R.; Cain, G. A. J . Am.
Chem. Soc. 1990, 112, 5220.
(3) Newcombe, N. J .; Fang, Y.; Vijn, R. J .; Hiemstra, H.; Speckamp,
W. N. J . Chem. Soc., Chem. Commun. 1994, 767.
(14) Klaver, W. J .; Hiemstra, H.; Speckamp W. N. J . Am. Chem.
Soc. 1989, 111, 2588.
S0022-3263(97)01510-7 CCC: $14.00 © 1997 American Chemical Society

Synthesis of the Oxindole Alkaloid Gelsedine
J . Org. Chem., Vol. 62, No. 25, 1997 8863
Sch em e 1
Sch em e 2a
a
Conditions: (a) NaBH4, EtOH, -15 °C, 1 h, then 1 M H2SO4
in EtOH, -25 °C f rt; (b) K2CO3, MeOH, rt, 1 h; (c) (1) LDA, THF,
-78 °C, then -25 °C, 1 h; (2) 1-bromo-2,3-butadiene, -78 °C, 4 h,
then rt, 18 h; (d) (1) LDA, THF, -78 °C, then -25 °C, 1 h; (2)
1-iodo-3-butyne, -117 °C, 6 h, then rt, 18 h; (e) (1) LDA, THF,
-78 °C, then -25 °C, 1 h; (2) propargyl bromide, -78 °C, 4 h,
then rt, 18 h; (f) CuI, i-Pr2NH, (CH2O)n, 1,4-dioxane, reflux, 18 h.
which was expected to cyclize on reaction with the proper
π-nucleophile to give the bicyclic skeleton 9. The early
stages of this strategy bear resemblance to our total
synthesis of the indole alkaloid peduncularine.14
In this paper, we report an efficient synthesis of
enantiopure bicyclic ketone 8 starting from (S)-malic acid.
Our approach features an efficient allene-terminated
N-acyliminium cyclization.
Sch em e 3a
Resu lts a n d Discu ssion
At the onset of our studies, we planned to apply an
alkyne-terminated N-acyliminium ion cyclization as the
key step to arrive at the 7-azabicyclo[4.2.1]nonane skel-
eton of ketone 9. Precedent for this type of cyclization
is available.15 The required starting material 11 was
synthesized from (S)-malic acid using a literature route
(Scheme 2).16 Regioselective reduction of 11 with NaBH4,
immediately followed by acidic ethanolysis, produced a
mixture of acetate 12 and its deacetylated product 13.
Complete deacylation was effected by treatment of the
crude mixture with K2CO3 in methanol, giving alcohol
13 as an 80:20 mixture of C-5 epimers. The crucial
alkylation reaction of the dianion from 13 (generated by
using 2.1 equiv of LDA) with 1-iodo-3-butyne at a reaction
temperature of -117 °C gave the desired alkyne 14 in
an unsatisfactory yield of 29%. Despite extensive ex-
perimentation this yield could not be improved, as higher
temperatures probably gave increased levels of hydrogen
a
Conditions: (a) (1) HCO2H, 85 °C; (2) 50% NH3 in MeOH, rt,
1 h; Nu-
)
-O2CH.
iodide elimination from the alkylating agent. On the
positive side, the alkylation at C-3 occurred exclusively
trans with respect to the stereocenter at C-4.
With the desired alkyne 14 in hand, its N-acyliminium
cyclization was studied. This process required prolonged
heating of 14 in formic acid for 60 h at 85 °C. The
resulting product was directly deformylated with am-
monia in methanol to give the expected ketone 9 as the
only isolable product in 52% yield as a nicely crystalline
solid (Scheme 3). The structure of 9 was proven through
X-ray crystallography (Figure 1).
(15) (a) Racemic synthesis of a 7-azabicyclo[4.2.1]nonane system via
N-acyliminium ion-alkyne cyclization: Wijnberg, J . B. P. A.; Speck-
amp, W. N. Tetrahedron 1978, 34, 2579. Other racemic syntheses of
these bicyclic systems: (b) Malpass, J . R. J . Chem. Soc., Chem.
Commun. 1972, 1246. (c) Newman, H.; Fields, T. L. Tetrahedron 1972,
28, 4051. (d) Mondon, A.; Aumann, G.; Oelrich, E. Chem. Ber. 1972,
105, 2025. (e) Coates, J . E.; Casy, A. F. J . Org. Chem. 1974, 39, 3044.
(f) Klaver, W. J .; Moolenaar, M. J .; Hiemstra, H.; Speckamp, W. N.
Tetrahedron 1988, 44, 3805. (g) Klaver, W. J .; Hiemstra, H.; Speckamp,
W. N. Tetrahedron 1988, 44, 6729. Enantiopure synthesis of this
bicyclic system: (h) Klaver, W. J .; Hiemstra, H.; Speckamp, W. N.
Tetrahedron Lett. 1987, 28, 1581.
Both the low alkylation and the moderate cyclization
yield described above led us to search for alternative ways
to arrive at ketone 9. It occurred to us that cationic
cyclization of allene 15 should lead to the same ketone 9
(Scheme 3). There is one indication in the literature that
(17) (a) Schoemaker, H. E.; Boer-Terpstra, T.; Dijkink, J .; Speckamp,
W. N. Tetrahedron 1980, 36, 143. (b) Nossin, P. M. M.; Speckamp, W.
N. Tetrahedron Lett. 1981, 22, 3289. (c) Nossin, P. M. M.; Hamersma,
J . A. M.; Speckamp, W. N. Tetrahedron Lett. 1982, 23, 3807. (d) Nossin,
P. M. M. Ph.D. Thesis, University of Amsterdam, 1983.
(16) Louwrier, S.; Ostendorf, M.; Boom, A.; Hiemstra, H.; Speckamp,
W. N. Tetrahedron 1996, 52, 2603.

8864 J . Org. Chem., Vol. 62, No. 25, 1997
Beyersbergen van Henegouwen and Hiemstra
Sch em e 5a
F igu r e 1. Molecular structure of 9 determined by X-ray
crystallography.
Sch em e 4
a
Conditions: (a) HOCH2CH2OH, p-TsOH, reflux; (b) (1) (ClCO)2,
DMSO, CH2Cl2, -78 °C, 2 h; (2) Et3N, rt, 15 min; (c) Ph3PMeBr,
n-BuLi, THF, 0 °C, then 18, reflux, 18 h; (d) BH3‚SMe2, 0 °C f rt,
2 h, then NaOH/H2O2; (e) NaH, MeI, THF, rt, 18 h; (f) Na/NH3,
THF, -78 °C; (g) NaH, ClCO2Me, THF, rt, 18 h; (h) EtMgCl, THF,
-78 °C, 0.5 h; (i) CF3CO2H, Et3SiH, CH2Cl2, 0 °C, 2 h, then rt, 1
h.
the internal double bond of the allene from participating
in the π-cyclization process.
an allene may be somewhat more reactive than an alkyne
in N-acyliminium cyclization processes leading to the
same ketone, although this particular example pertains
to six-membered ring formation (Scheme 4).17,18 For the
synthesis of 15, the dianion of 13 was first alkylated with
propargyl bromide the give alkyne 16 in 58% yield. The
latter alkyne was then subjected to a Crabbe´ homologa-
tion19 to provide the desired allene 15 in 75% yield. A
more direct route to 15 involved the alkylation of 13 with
1-bromo-2,3-butadiene20 to furnish the allene in a satis-
factory 64% yield. Moreover, these alkylations to 15 and
16 could be conveniently carried out at temperatures not
lower than -78 °C and proceeded with complete trans
selectivity with respect to the C-4 stereocenter.
With a convenient access to ketone 9 secured, the
further steps of our projected route to gelsedine were
investigated. To introduce the required hydroxymethyl
functionality, ketone 9 was protected as a dioxolane and
then subjected to Swern oxidation affording ketone 18
(Scheme 5). Wittig olefination to 19 and subsequent
hydroboration with the borane dimethyl sulfide complex
and oxidative workup gave the desired alcohol 20 with
complete stereoselectivity in the desired sense. Its
stereochemistry was proven by hydrolysis of the diox-
olane in 20, which gave hemiacetal 21 in quantitative
yield.
The key cationic cyclization of allene 15 proceeded
smoothly at 85 °C in formic acid to furnish in only 18 h
79% of ketone 9 after subsequent deformylation (Scheme
3). Thus, we have now developed a fairly direct synthesis
of the enantiopure bicyclic ketone 9 via a novel and
efficient N-acyliminium allene cyclization. It is interest-
ing to note here that the homologous alkyne and allene
of the literature system (Scheme 4) behave in a com-
pletely different fashion.17 Whereas the alkyne cleanly
led to the expected seven-membered ring ketone, the
allene gave a mixture containing no seven-membered
ring products. The geometry of the bicyclic transition
state leading to 9 clearly plays a crucial role, preventing
The hydroxyl group in 20 was then protected provi-
sionally as a methyl ether to study the introduction of
the C-8 ethyl substituent. The carbonyl group in N-
benzyllactam 22 was unreactive toward ethylmagnesium
chloride under several different conditions, so that acti-
vation of the carbonyl toward nucleophilic addition was
required. Therefore, 22 was debenzylated by treatment
with sodium in ammonia, and the product 23 was
subsequently treated with methyl chloroformate to give
the desired carbamate 24. As expected, 24 smoothly
reacted with ethylmagnesium chloride, even at -78 °C.
Although the product, hemiaminal 25, was stable at room
temperature, its purification on silica gel gave partial
five-membered ring-opening to the corresponding ketone.
Hence, the crude product was immediately treated with
trifluoroacetic acid, giving the N-acyliminium ion, which
was reduced in situ with triethylsilane to produce car-
bamate 26 as a single stereoisomer.21 As a bonus, the
(18) For intermolecular reactions of N-acyliminium ions with al-
lenes, see: (a) Danheiser, R. L.; Kwasigroch, C. A.; Tsai, Y.-M. J . Am.
Chem. Soc. 1985, 107, 7233. (b) Prasad, J . S.; Liebeskind, L. S.
Tetrahedron Lett. 1988, 29, 4257.
(19) Crabbe´, P.; Fillion, H.; Andre, K.; Luche, J . L. J . Chem. Soc.,
Chem. Commun. 1979, 859.
(20) Pornet, J .; Randrianoelina B.; Miginiac, L. J . Organomet. Chem.
1979, 174, 1.
(21) Reduction with Et3SiH/BF3‚OEt2: Dijkink, J .; Eriksen, K.;
Goubitz, K.; Van Zanden, M. N. A.; Hiemstra, H. Tetrahedron:
Asymmetry 1996, 7, 515.

Synthesis of the Oxindole Alkaloid Gelsedine
J . Org. Chem., Vol. 62, No. 25, 1997 8865
solution of diisopropylamine (11.2 mL, 80.36 mmol) in THF
(100 mL) was added under nitrogen at -78 °C a 1.6 M solution
of n-BuLi in hexane (50.2 mL, 80.36 mmol). After the mixture
was stirred for 15 min at -78 °C, a solution of the epimeric
mixture 13 (9.00 g, 38.25 mmol) in THF (20 mL) was added.
The reaction mixture was stirred for 1 h at -20 °C and then
cooled to -117 °C. A solution of 1-iodobutyne (16.74 g, 93.0
mmol) in THF (10.0 mL) was slowly added. The reaction
mixture was stirred for 6 h at -117 °C, allowed to warm
slowly, stirred for 18 h at rt, and then poured onto saturated
aqueous NH4Cl (100 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 50 mL). The combined organic layers were
washed with water (100 mL), dried (MgSO4), and concentrated
in vacuo. The residue was chromatographed (first CH2Cl2/
acetone 6:1, then CH2Cl2/acetone 2:1 to recover unreacted 13)
to give 14 (3.19 g, 29%) as a light-yellow oil. Major isomer:
Rf 0.44 (CH2Cl2/acetone 6:1); IR 3290, 2928, 1681; 1H NMR (400
MHz) 1.18 (t, J ) 7.6 Hz, 3H), 1.74 (m, 1H), 2.04 (t, J ) 2.6
Hz, 1H), 2.16 (m, 1H), 2.46 (m, 2H), 2.76 (br, 1H), 3.52 (m,
2H), 4.02 (d, J ) 14.8 Hz, 1H), 4.02 (s, 1H), 4.47 (d, J ) 2.3
Hz, 1H), 4.94 (d, J ) 14.8 Hz, 1H), 7.28 (m, 5H); 13C NMR
(100 MHz) 15.3, 16.7, 28.5, 43.4, 49.8, 64.1, 69.4, 75.8, 83.8,
dioxolane was hydrolyzed during the aqueous workup.
The stereochemistry of 26 was proven by NOE measure-
ments (a NOE of 10.4% was observed between H-8 and
H-9).
In conclusion, we have prepared in an efficient way
an advanced synthetic intermediate in our projected
synthesis of enantiopure ent-gelsedine. Four new ste-
reocenters have been created with complete control from
only one in the starting material (S)-malic acid. A novel
N-acyliminium allene cyclization served to arrive at the
required 7-azabicyclo[4.2.1]nonane-4,8-dione skeleton.
The additional functionalities including the C-8 ethyl and
the C-9 hydroxymethyl were introduced with complete
stereocontrol. Remaining challenges include the stereo-
selective introduction of the oxindole moiety and closure
of the tetrahydropyran ring, which we will report on in
due course.
Exp er im en ta l Section
93.6, 127.8, 128.1, 128.6, 135.9, 173.9; HRMS calcd for C17H21
NO3 287.1521, found 287.1592.
-
Gen er a l In for m a tion . All reactions involving oxygen- or
moisture-sensitive compounds were carried out under a dry
N2 atmosphere. Unless otherwise noted, reagents were added
by syringe. Column chromatography was performed with
Merck 60 (230-400 mesh) silica gel using the procedure of
Still.22 Thin-layer chromatography (TLC) was performed with
Merck F-254 silica gel plastic sheets. All starting materials
were obtained from commercial suppliers and used without
further purification. THF and ether were distilled from
sodium/benzophenone immediately prior to use. Dichlo-
romethane (CH2Cl2), benzene, triethylamine, and diisopropy-
lamine were distilled from CaH2 immediately prior to use.
Dimethyl sulfoxide (DMSO) was dried and stored over 4 Å
molecular sieves. IR spectra (cm-1) were measured as thin
films on NaCl plates unless otherwise noted. 1H NMR and
13C NMR spectra were measured as solutions in CDCl3, and
chemical shifts are expressed in ppm relative to internal CHCl3
(7.26 ppm). Mass spectra were measured using electron
impact (EI) mass spectrometry, unless otherwise noted. El-
emental analyses were performed at the University of Am-
sterdam by J . Dijkink.
(4S ,5R )-1-B e n zy l-5-e t h o x y -4-h y d r o x y -2-p y r r o lid i-
n on e a n d (4S,5S) Ep im er (13). To a stirred solution of 1116
(32.6 g, 0.132 mol) in EtOH (850 mL) at -35 °C was added
NaBH4 (25.00 g, 0.661 mol). An ethanolic solution of H2SO4
(ca. 3.5 mL, 4 M) was added dropwise at -35 °C to catalyze
the reduction. After the reaction mixture was stirred for 1 h
at -15 °C, it was cooled to -50 °C, and an ethanolic solution
of H2SO4 (ca. 585 mL, 1 M) was added over a period of 30 min
(the temperature was maintained below -25 °C). After the
reaction mixture was stirred for 18 h at rt, it was poured onto
saturated aqueous NaHCO3 (400 mL), H2O was added (1200
mL), and the aqueous layer was extracted with CH2Cl2 (4 ×
400 mL). The combined organic layers were washed with H2O
(4 × 600 mL), dried (MgSO4), and concentrated in vacuo to
give a colorless oil of a mixture of 12 and 13. To complete the
deacetylation, K2CO3 (3.65 g, 0.0264 mol) was added to a
solution of this oil in MeOH (50 mL). After the solution was
stirred for 1 h at rt, it was poured onto saturated aqueous NH4-
Cl (50 mL). Extraction with CH2Cl2 (3 × 50 mL), followed by
drying (MgSO4) and concentration of the combined organic
layers in vacuo, gave pure 13 (27.64 g, 89%) as a yellowish oil
(80:20 mixture of epimers). Major isomer: Rf 0.36 (CH2Cl2/
acetone 2:1); IR 3393, 2929, 1682; 1H NMR (400 MHz) 1.17 (t,
J ) 7.0 Hz, 3H), 2.02 (br, 1H), 2.33 (dd, J ) 1.4, 17.6 Hz, 1H),
2.89 (ddd, J ) 0.9, 6.3, 17.6 Hz, 1H), 3.45 (m, 2H), 3.53 (m,
2H), 4.06 (d, J ) 15.0 Hz, 1H), 4.24 (t, J ) 4.7 Hz, 1H), 4.97
(d, J ) 15.0 Hz, 1H), 7.29 (m, 5H); 13C NMR (100 MHz) 15.0,
38.8, 43.7, 53.3, 68.6, 95.0, 127.3, 127.8, 128.5, 135.8; HRMS
calcd for C13H17NO3 235.1208, found 235.1192.
(3S,4S,5R)-1-Ben zyl-5-eth oxy-4-h yd r oxy-3-(bu ta -2,3-d i-
en yl)-2-p yr r olid in on e a n d (3S,4S,5S) Ep im er 15. Alky-
lation of 13 (1.60 g, 6.8 mmol) with 1-bromo-2,3-butadiene (1.50
g, 11.3 mmol) (4 h at -78 °C, then 18 h at rt) gave after
chromatography (CH2Cl2/acetone 6:1) 15 (1.26 g, 64%) as a
light-yellow oil. Major isomer: Rf 0.47 (CH2Cl2/acetone 6:1);
1
IR 3394, 1956, 1678; H NMR (400 MHz) 1.16 (t, J ) 7.0 Hz,
3H), 2.25 (m, 1H), 2.46 (m, 1H), 2.55 (br, 1H), 2.60 (m, 1H),
3.50 (m, 2H), 4.01 (s, 1H), 4.04 (d, J ) 15.0 Hz, 1H), 4.45 (d,
J ) 1.5 Hz, 1H), 4.72 (m, 2H), 5.19 (q, J ) 6.7 Hz, 1H), 4.92
(d, J ) 14.9 Hz, 1H), 7.26 (m, 5H); 13C NMR (100 MHz) 15.3,
28.4, 43.5, 50.5, 63.9, 74.6, 75.7, 87.4, 93.7, 127.5, 128.1, 128.1,
128.2, 128.6, 136.0, 174.0, 209.1; HRMS calcd for C17H21NO3
287.1521, found 287.1515.
(3S,4S,5R)-1-Ben zyl-5-eth oxy-4-h ydr oxy-3-(pr op-2-yn yl)-
2-p yr r olid in on e a n d (3S,4S,5S) Ep im er (16). Alkylation
of 13 (11.60 g, 49.3 mmol) with 80% propargyl bromide in
toluene (8.28 mL, 74.3 mmol) (4 h at -78 °C, then 18 h at rt)
gave after chromatography (CH2Cl2/acetone 6:1) 16 (7.82 g,
58%) as a light-yellow oil. Major isomer: Rf 0.71 (CH2Cl2/
acetone 2:1); IR 3292, 2929, 1680; 1H NMR (400 MHz) 1.15 (t,
J ) 7.0 Hz, 3 H), 2.01 (t, J ) 2.2 Hz, 1 H), 2.52 (m, 2H), 2.68
(d, J ) 15 Hz, 1H), 3.51 (m, 2H), 3.99 (br, 1H), 4.01 (d, J )
14.9 Hz, 1H), 4.18 (s, 1H), 4.49 (d, J ) 2.6 Hz, 1H), 4.87 (d, J
) 14.9 Hz, 1H), 7.24 (m, 5H); 13C NMR (100 MHz) 15.2, 18.2,
43.3, 49.0, 63.9, 70.5, 74.6, 80.8, 93.2, 127.4, 128.0, 128.5, 128.6,
128.6, 135.6, 172.3; HRMS calcd for C16H19NO3 273.1365, found
273.1375.
(3S,4S,5R)-1-Ben zyl-5-eth oxy-4-h yd r oxy-3-(bu ta -2,3-d i-
en yl)-2-p yr r olid in on e a n d (3S,4S,5S) Ep im er (15). To a
stirred solution of 16 (7.73 g, 28.3 mmol) in 1,4-dioxane (100
mL) were added copper(I) iodide (2.69 g, 14.1 mmol), diiso-
propylamine (7.95 mL, 56.6 mmol), and paraformaldehyde
(1.27 g, 70.1 mmol). After the reaction mixture was stirred
for 18 h at reflux, it was cooled to rt and filtered over Celite.
The 1,4-dioxane was evaporated, and the residue was taken
up in CH2Cl2 (250 mL). The organic layer was washed with a
10% solution of ammonia in brine (2 × 100 mL), water (pH )
2, 2 × 100 mL), water (100 mL), dried (MgSO4), and concen-
trated in vacuo. The residue was chromatographed (CH2Cl2/
acetone 6:1) to give 15 (6.07 g, 75%) as a light-yellow oil.
(1S ,6R ,9S )-7-Be n zyl-9-h yd r oxy-7-a za b icyclo[4.2.1]-
n on a n e-4,8-d ion e (9). A solution of 14 (3.19 g, 11.10 mmol)
in HCO2H (55 mL) was stirred at 85 °C for 2.5 days and then
concentrated in vacuo. The residue was dissolved in a 50%
methanolic NH3 solution (50 mL). After this solution was
stirred for 1 h at rt, the MeOH was evaporated and the residue
was chromatographed (CH2Cl2/acetone 1:1) to give 9 as a white
crystalline solid, which was recrystallized from EtOAC to give
Gen er a l P r oced u r e for Alk yla tion of 12: (3S,4S,5R)-
1-Ben zyl-5-eth oxy-4-h yd r oxy-3-(bu t-3-yn yl)-2-p yr r olid i-
n on e a n d (3S,4S,5S) Ep im er (14). To a mechanically stirred
(22) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

8866 J . Org. Chem., Vol. 62, No. 25, 1997
Beyersbergen van Henegouwen and Hiemstra
white needles (1.49 g, 52%): mp 208-210 °C; [R]20 +16.9 (c
(1S,6R,9R)-7-Ben zyl-4,4-(et h ylen ed ioxy)-9-(h yd r oxy-
m et h ylen e)-7-a za b icyclo[4.2.1]n on a n -8-on e (20). To
BH3‚Me2S (2.80 mL of a 1 M solution in THF, 2.80 mmol) was
added at 0 °C a solution of 19 (1.25 g, 4.16 mmol) in THF (3
mL). After being stirred for 2 h at rt, the solution was cooled
to 0 °C and subsequently treated with 3 M aqueous NaOH
(5.60 mL) and 35% aqueous H2O2 (2.40 mL). The resulting
solution was stirred for 1 h at rt and then poured onto water
(40 mL). The aqueous layer was extracted with CH2Cl2 (3 ×
40 mL). The combined organic layers were dried (MgSO4) and
concentrated in vacuo. The residue was chromatographed
(CH2Cl2/acetone 1:1) to give 20 (1.17 g, 89%) as a colorless oil:
D
0.99, CHCl3); Rf 0.40 (CH2Cl2/acetone 1:1); IR 3403, 1695, 1652;
1H NMR (400 MHz) 1.76 (m, 1H), 2.17 (m, 1H), 2.21 (br, 1H),
2.37 (dd, J ) 4.6, 8.9 Hz, 2H), 2.44 (dd, J ) 4.8, 16.1 Hz, 1H),
2.54 (dd, J ) 2.1, 16.1 Hz, 1H), 2.75 (dd, J ) 3.3, 4.5 Hz, 2H),
3.63 (dd, J ) 2.1, 4.8 Hz, 1H), 3.78 (s, 1H), 4.26 (d, J ) 15.1
Hz, 1H), 4.95 (d, J ) 15.1 Hz, 1H), 7.35 (m, 5H); 13C NMR
(100 MHz) 24.8, 39.9, 44.1, 44.4, 51.2, 60.6, 74.7, 128.0, 128.1,
128.9, 135.7, 174.3, 209.1; HRMS calcd for C15H17NO3 259.1208,
found 259.1207. Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61;
N, 5.40. Found: C, 69.41; H, 6.86; N, 5.20. An X-ray crystal
structure was obtained: monoclinic, P21, a ) 7.0609(6) Å, b )
9.7810(7) Å, c ) 9.758(1) Å, V ) 667.3(1) Å3, Z ) 2, Dx ) 1.29
g cm-3, λ(Cu KR) ) 1.5418 Å, µ(Cu KR) ) 6.95 cm-1, F (000) )
276, -20 °C. Final R ) 0.042 for 1297 observed reflections.
(1S,6R,9S)-7-Ben zyl-4,4-(et h ylen ed ioxy)-9-h yd r oxy-7-
a za bicyclo[4.2.1]n on a n -8-on e (17). A solution of 9 (1.59 g,
6.13 mmol), ethylene glycol (1.03 mL, 18.38 mmol), and
p-toluenesulfonic acid monohydrate (0.175 g, 0.919 mmol) in
benzene (12 mL) was refluxed, and benzene (4 × 8 mL) was
distilled off. The reaction mixture was cooled and then poured
onto saturated aqueous NaHCO3 (40 mL) and was extracted
with CH2Cl2 (3 × 40 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. This gave pure 17
(1.84 g, 99%) as a white solid, which was used without further
[R]20 +73.4 (c 1.01, CHCl3); Rf 0.33 (CH2Cl2/acetone 1:1); IR
D
1
3010, 1679; H NMR (400 MHz) 1.73 (m, 3H), 1.90 (m, 2H),
2.29 (dd, J ) 2.9, 16.1 Hz, 1H), 2.60 (m, 1H), 2.69 (m, 1H),
3.54 (dt, J ) 3.2, 6.7 Hz, 1H), 3.90 (m, 5H), 4.09 (m, 2H), 5.16
(d, J ) 15.2 Hz, 1H), 7.27 (m, 5H); 13C NMR (100 MHz) 20.5,
32.9, 37.8, 42.9, 43.2, 44.6, 54.9, 59.0, 63.7, 64.1, 110.7, 127.3,
127.8, 128.5, 136.2, 176.2; HRMS calcd for C18H23NO4 317.1627,
observed 317.1627.
(1S,6R,9R)-6-Ben zyl-1-h yd r oxy-10-oxa -6-a za t r icyclo-
[5.3.1.04,8]d eca n -5-on e (21). A solution of 20 (0.040 g, 0.13
mmol) in THF/2 M HCl (1:1, 0.50 mL) was stirred for 4 h and
then poured onto saturated aqueous NaHCO3 (10 mL) and was
extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. This
purification: mp 178-180 °C; [R]20 +47.0; Rf 0.50 (acetone
D
1:1); IR 3406, 2951, 1674; H NMR (400 MHz) 1.64 (m, 2H),
gave pure 21 (0.032 g, 92%) as a colorless oil: [R]20
+72.9 (c
1
D
1.80 (dd, J ) 5.2, 15.2 Hz, 1H), 1.91 (m, 3H), 2.30 (br, 1H),
2.61 (t, J ) 4.1 Hz, 1H), 3.44 (dd, J ) 1.4, 5.0 Hz, 1H), 3.58
(m, 4H), 3.95 (d, J ) 15.3 Hz, 1H), 4.41 (s, 1H), 5.05 (d, J )
15.3 Hz, 1H), 7.29 (m, 5H); 13C NMR (100 MHz) 22.6, 32.3,
37.4, 43.4, 51.2, 61.9, 63.8, 64.3, 71.6, 110.3, 127.5, 127.9, 128.7,
136.01, 175.5; HRMS calcd for C17H21NO4 303.1470, found
303.1468.
1.38, CHCl3); R 0.32 (CH Cl /acetone 1:1); IR 3018, 2934, 1677;
f
2
2
1H NMR (400 MHz) 1.95 (m, 5H), 2.51 (t, J ) 8.3 Hz, 1H),
2.55 (s, 1H), 2.80 (m, 1H), 3.75 (t, J ) 7.4 Hz, 1H), 4.02 (m,
2H), 4.12 (dd, J ) 1.8, 11.3 Hz), 5.00 (d, J ) 14.9 Hz, 1H),
7.30 (m, 5H); 13
C NMR (100 MHz) 23.1, 34.8, 38.3, 39.7, 43.6,
44.9, 52.8, 62.3, 97.1, 127.8, 128.2, 128.9, 136.2, 176.3; HRMS
calcd for C16H19NO3 273.1365, observed 273.1380.
(1S,6R,9R)-7-Ben zyl-4,4-(et h ylen ed ioxy)-9-(m et h oxy-
m eth ylen e-)7-a za bicyclo[4.2.1]n on a n -8-on e (22). To a
stirred solution of 20 (0.71 g, 2.29 mmol) in THF (5 mL) was
added 60% NaH in mineral oil (0.28 g, 6.89 mmol) at rt. After
the mixture was stirred for 0.5 h, methyl iodide (0.43 mL, 6.89
mmol) was added. The solution was stirred for 18 h and then
poured onto saturated aqueous NH4Cl (15 mL). The aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The combined
organic layers were dried (MgSO4) and concentrated in vacuo.
The residue was chromatographed (CH2Cl2/acetone 2:1) to give
22 (0.69 g, 91%) as a colorless oil: [R]20D +67.6 (c 1.00, CHCl3);
Rf 0.49 (CH2Cl2/acetone 2:1); IR 3005, 2931, 1678; 1H NMR (400
MHz) 1.69 (m, 3H), 1.85 (m, 2H), 2.23 (dd, J ) 3.0, 16.1 Hz,
1H), 2.62 (m, 2H), 3.28 (s, 3H), 3.47 (m, 1H), 3.67 (m, 1H),
3.85 (m, 6H), 5.11 (d, J ) 15.2 Hz, 1H), 7.23 (m, 5H); 13C NMR
(100 MHz) 20.6, 33.1, 37.8, 42.2, 42.9, 43.4, 55.1, 58.8, 64.0,
64.1, 68.9, 110.8, 127.4, 127.8, 128.6, 136.3, 176.3; HRMS calcd
for C19H25NO4 331.1783, found 331.1766.
(1S,6R)-7-Ben zyl-4,4-(eth ylen edioxy)-7-azabicyclo[4.2.1]-
n on a n e-8,9-d ion e (18). To a stirred solution of oxalyl
chloride (0.83 mL, 9.49 mmol) in CH2Cl2 (10 mL) was added
DMSO (1.44 mL, 20.28 mmol) at -78 °C. After the reaction
mixture was stirred for 5 min, 17 (1.81 g, 5.96 mmol) was
added, and the reaction mixture was stirred for 2 h at -78
°C. Then Et3N (6.21 mL, 44.62 mmol) was added, and the
reaction mixture was allowed to warm to rt, stirred at this
temperature for 15 min, and poured onto saturated aqueous
NH4Cl (40 mL). The organic layer was separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 40 mL). The
combined organic layers were dried (MgSO4) and concentrated
in vacuo. The residue was chromatographed (EtOAc) to give
18 (0.172 g, 96%) as a colorless oil: [R]20D +48.2 (c 0.89, CHCl3);
Rf 0.47 (EtOAc); IR 3018, 1776, 1692; 1H NMR (400 MHz) 1.75
(m, 1H), 1.88 (m, 2H), 2.09 (m, 3H), 3.01 (dd, J ) 3.5, 6.0 Hz,
1H), 3.73 (dd, J ) 2.6, 4.4 Hz, 1H), 3.90 (m, 4H), 4.00 (d, J )
14.9 Hz, 1H), 5.24 (d, J ) 14.9 Hz, 1H), 7.29 (m, 5H); 13C NMR
(100 MHz) 24.2, 33.1, 35.9, 43.3, 51.4, 61.6, 64.1, 64.7, 109.3,
128.02, 128.3, 128.9, 135.0, 171.5, 206.0; HRMS calcd for
C17H19NO4 301.1314, found 301.1301.
(1S,6R)-7-Ben zyl-4,4-(et h ylen ed ioxy)-9-m et h ylen e-7-
a za bicyclo[4.2.1]n on a n -8-on e (19). To a stirred solution of
methyltriphenylphosphonium bromide (3.24 g, 9.07 mmol) in
THF (25 mL) was added at 0 °C a 1.6 M solution of n-BuLi in
hexane (5.39 mL, 8.36 mmol). After 25 min, a solution of 18
(1.66 g, 5.56 mmol) in THF (5 mL) was added. The reaction
mixture was refluxed for 18 h and then poured onto saturated
aqueous NH4Cl (40 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 40 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. The residue was
chromatographed (CH2Cl2/acetone 4:1) to give 19 (1.36 g, 82%)
as a white solid: mp 138-140 °C; [R]20D +17.3 (c 1.00, CHCl3);
Rf 0.49 (CH2Cl2/acetone 4:1); IR 3009, 1693, 1672; 1H NMR (400
MHz) 1.75 (m, 2H), 1.87 (m, 2H), 2.02 (m, 1H), 2.18 (ddd, J )
1.0, 2.7, 14.7 Hz, 1H), 3.14 (dd, J ) 0.9, 6.6 Hz, 1H), 3.87 (m,
6H), 4.98 (s, 2H), 5.13 (d, J ) 15.3 Hz, 1H), 7.27 (m, 5H); 13C
NMR (100 MHz) 25.4, 32.9, 40.2, 43.4, 47.3, 58.6, 63.2, 64.6,
108.2, 110.2, 127.5, 128.0, 128.7, 136.2, 144.9, 175.9; HRMS
calcd for C18H21NO3 299.1521, found 299.1532. Anal. Calcd
for C18H21NO3: C, 72.22; H, 7.07; N, 4.68. Found: C, 71.69;
H, 6.92; N, 4.69.
(1S,6R,9R)-4,4-(Eth ylen ed ioxy)-9-(m eth oxym eth ylen e)-
7-a za bicyclo[4.2.1]n on a n -8-on e (23). To a deep blue solu-
tion of sodium (0.174 g, 7.57 mmol) in condensed ammonia
(25 mL) was added 22 (0.683 g, 2.06 mmol) in THF (5 mL) at
-78 °C. The solution was stirred for 15 min at -78 °C, and
then NH4Cl (0.440 g, 8.22 mmol) was added. The ammonia
was allowed to evaporate slowly at rt by passing a stream of
nitrogen over the solution. The THF was evaporated in vacuo,
the residue was taken up in warm CH2Cl2 (40 mL) and filtered,
and the solids were washed with warm CH2Cl2 (20 mL). The
filtrate was concentrated in vacuo to give 23 (0.410 g, 83%) as
a white crystalline solid: mp 145-146.5 °C; [R]20 +49.8 (c
D
0.99, CHCl3); Rf 0.53 (acetone); IR 3295, 2943, 1704, 1676; 1H
NMR (400 MHz) 1.66 (m, 2H), 1.78 (m, 2H), 2.00 (dq, J ) 3.5,
16.0 Hz, 2H), 2.45 (m, 1H), 2.77 (m, 1H), 2.86 (s, 3H), 3.78 (m,
7H), 6.98 (s, 1H); 13C NMR (100 MHz) 20.2, 32.9, 42.5, 42.9,
43.4, 52.9, 58.7, 63.7, 64.1, 68.9, 111.0, 179.5; HRMS calcd for
C12H18NO4 241.1314, found 241.1314. Anal. Calcd for
C12H19NO4: C, 59.73; H, 7.94; N, 5.81. Found: C, 59.94; H,
8.16; N, 5.69.
(1S,6R,9R)-4,4-(Eth ylen ed ioxy)-7-(m eth oxyca r bon yl)-
9-(m et h oxym et h ylen e)-7-a za b icyclo[4.2.1]n on a n -8-on e
(24). To a stirred solution of 23 (0.200 g, 0.829 mmol) in THF
(3 mL) were added 60% NaH in mineral oil (0.133 g, 3.32

Synthesis of the Oxindole Alkaloid Gelsedine
J . Org. Chem., Vol. 62, No. 25, 1997 8867
mmol) and methyl chloroformate (0.255 mL, 3.32 mmol) at rt.
The solution was stirred for 18 h and then poured onto
saturated aqueous NH4Cl (10 mL). The aqueous layer was
extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. The
residue was chromatographed (CH2Cl2/acetone 3:1) to give 24
onto saturated aqueous NaHCO3 (10 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. The
residue was chromatographed (EtOAc/hexanes 3:1) to give 26
(0.095 g, 54%) as a colorless oil: [R]20 +32.2 (c 1.01, CHCl3);
D
Rf 0.44 (EtOAc/hexanes 3:1); IR 3021, 2955, 1691; 1H NMR
(400 MHz) 0.96 (t, J ) 7.4 Hz, 3H), 1.55 (m, 3H), 1.84 (dq, J
) 4.3, 15.2 Hz, 1H), 2.42 (m, 2H), 2.50 (m, 1H), 2.60 (m, 1H),
2.91 (m, 2H), 3.32 (m, 5H), 3.58 (m, 1H), 3.71 (s, 3H), 4.18 (s,
1H); 13C NMR (100 MHz) 11.7, 19.9, 20.7, 38.3, 41.8, 44.5, 46.2,
(0.205 g, 82%) as a colorless oil: [R]20 +4.3 (c 1.01, CHCl3);
D
Rf 0.52 (CH2Cl2/acetone 3:1); IR 2954, 1790, 1716; 1H NMR (400
MHz) 1.77 (m, 3H), 1.86 (m, 1H), 1.95 (dd, J ) 3.2, 16.0 Hz,
1H), 2.48 (dd, J ) 3.6, 7.2 Hz, 1H), 2.72 (m, 2H), 3.33 (s, 3H),
3.65 (m, 2H), 3.82 (m, 9H), 4.36 (quintet, J ) 3.4 Hz, 1H); 13
C
52.2, 56.2, 59.2, 65.0, 69.3, 157.3, 212.6; HRMS calcd for C14H28
NO4 269.1627, found 269.1638.
-
NMR (100 MHz) 20.8, 33.5, 38.5, 40.7, 44.8, 53.4, 56.9, 58.9,
63.9, 64.4, 68.7, 110.3, 151.7, 175.9; HRMS calcd for C14H21
NO6 299.1369, found 299.1358.
-
Ack n ow led gm en t. We gratefully acknowledge J .
Fraanje and K. Goubitz (Laboratory of Crystallography)
for determining the X-ray structure of ketone 9. We also
thank Professor W. N. Speckamp for fruitful discussions,
R. H. Balk for synthesizing a considerable amount of
ethoxy lactam 12, and W. F. J . Karstens for suggesting
the use of allene 13.
(1S,6R,8S,9R)-8-E t h yl-7-(m et h oxyca r b on yl)-9-(m et h -
oxym eth ylen e)-7-a za bicyclo[4.2.1]n on a n -4-on e (26). Eth-
ylmagnesium chloride (0.652 mL of a 2 M solution in THF,
1.30 mmol) was added to a solution of 24 (0.195 g, 0.651 mmol)
in THF (4 mL) at -78 °C. After the solution was stirred for
0.5 h at -78 °C, saturated aqueous NH4Cl (1 mL) was added.
The solution was allowed to warm to rt and then poured onto
more saturated aqueous NH4Cl (10 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. The
residue (0.197 g) was not purified but directly used in the
following reaction. To a solution of the residue in CH2Cl2 (1.20
mL) was added trifluoroacetic acid (0.300 mL, 3.91 mmol) at
0 °C and was stirred for 20 min at 0 °C. Then triethylsilane
(0.416 mL, 2.60 mmol) was added. After the solution was
stirred for 2 h at 0 °C and 1 h at rt, the solution was poured
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 9, 13-24, and 26 and X-ray data of compound 9
(43 pages). This material is contained in libraries on micro-
fiche, immediately follows this article in the microfilm version
of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
J O971510N