Synthesis of new bridged tetrahydro-β-carbolines and spiro-fused quinuclidines

Article abstract of DOI:10.1016/S0040-4020(01)00023-0

Two series of chemically related, conformationally restricted ring systems were synthesized. Bridged tetrahydro-β-carbolines, designed as selective 5-HT receptor ligands, were formed via Pictet-Spengler condensation of cyclic tryptamine precursors. Oxidation of the indole 2-position of the precursors followed by condensation with aldehydes produced spiro-cyclic quinuclidines, containing important muscarine receptor pharmacophores.

Full text of DOI:10.1016/S0040-4020(01)00023-0

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 2039±2049
Synthesis of new bridged tetrahydro-b-carbolines
and spiro-fused quinuclidines
²
Brigitte E. A. Burm, Christiaan Gremmen, Martin J. Wanner and Gerrit-Jan Koomen
p
Laboratory of Organic Chemistry, Institute of Molecular Chemistry, University of Amsterdam, Nieuwe Achtergracht 129,
NL-1018 WS Amsterdam, The Netherlands
Received 12 October 2000; revised 6 December 2000; accepted 21 December 2000
AbstractÐTwo series of chemically related, conformationally restricted ring systems were synthesized. Bridged tetrahydro-b-carbolines,
designed as selective 5-HT receptor ligands, were formed via Pictet±Spengler condensation of cyclic tryptamine precursors. Oxidation of the
indole 2-position of the precursors followed by condensation with aldehydes produced spiro-cyclic quinuclidines, containing important
muscarine receptor pharmacophores. q 2001 Elsevier Science Ltd. All rights reserved.
1
1
Conformationally restricted analogs of receptor substrates
have received much attention in medicinal chemistry. For
instance, the serotonin and muscarinic cholinergic receptors
are studied intensively by modi®cation of their ligands. The
introduction of rigidity in receptor ligands can result in
discrimination between several receptor subtypes and thus
contribute to the development of compounds that display
speci®c therapeutic activity with reduced side effects.
are important for muscarinic receptor binding. Although
these oxindoles have a completely different structure, from a
synthetic point of view they are closely related to the tetra-
hydro-b-carbolines discussed before.
As starting materials for the synthesis of conformationally
restricted ligands for both receptor families, we have
selected three tryptamines in which the aminoethyl side-
chain is incorporated in a heterocyclic ring (Scheme 1).
Application of the frequently used Pictet±Spengler conden-
Recognition of serotonin (5-hydroxytryptamine, 5-HT) by
1
2±14
5
-HT receptors can be attributed partly to the orientation of
the alkylamino sidechain. Some semi-rigid analogs of
-substituted tryptamines have provided insight into the
ligand recognition requirements for these receptor
sation
to these tryptamine analogs will produce the
anticipated tetrahydro-b-carbolines. Additionally, the
desired spiro-fused compounds can be obtained from
condensation reactions with aldehydes, when the indole
2-position is made unavailable for Pictet±Spengler conden-
sation by oxidation. Examples of this type of reaction with
2-hydroxytryptamine in the synthesis of natural products
5
1
±4
subtypes. Tetrahydro-b-carbolines can be seen as 5-HT
analogs, and their biological activity has been studied.
5
,6
Introduction of a carbon-bridge across the piperidine part
of the tetrahydro-b-carboline ring system as in Scheme 1
will result in increased rigidity and in particular the spatial
arrangement of the substituent at C-1 will be in¯uenced.
The muscarinic cholinergic class of receptors has proved to
be sensitive for conformationally restricted ligands. In
particular substituted quinuclidines ±1e0xhibit selective
7
muscarinic receptor binding properties
and we reasoned
that quinuclidines containing a spiro-fused oxindole as
shown in Scheme 1 are potential conformationally restricted
muscarine analogs. These spiro-fused indoles contain the
well-de®ned positions of pharmacophoric elements that
Keywords: Pictet±Spengler reaction; oxindoles; quinuclidines; spiro-
compounds.
p
Corresponding author. Tel.: 131-20-5256933; fax: 131-20-5255670;
e-mail: gjk@org.chem.uva.nl
Present address: Leiden Institute of Chemistry, Gorlaeus Laboratories,
P.O. Box 9502, NL-2300 RA Leiden, The Netherlands.
²
Scheme 1. mˆ1, 2; nˆ0, 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00023-0

2
040
B. E. A. Burm et al. / Tetrahedron 57 (2001) 2039±2049
Scheme 2. (i) (a) Indole, HOAc, re¯ux, 12 h; (b) LiAlH
NaOMe, MeOH; (b) Pd(OH) /C, EtOH, HOAc, 40 psi, 3 (58%), 5 (74%) (two steps).
4
, THF, re¯ux, 53% (two steps). (ii) DMSO, conc. HCl, rt, 2 (79%), 4 (79%), 6 (57%). (iii) (a) Indole,
2
1
5±17
can be found in the literature.
Oxidative rearrangement
the 2-position and subsequent elimination of dimethyl sul-
®de. Following this procedure, the cyclic tryptamines 1, 3
and 5 were oxidized to the corresponding 2-oxindoles 2, 4
of tetrahydro-b-carbolines offers an alternative route to
spiro-fused oxindoles, but this will not be discussed here.
(
(
both as mixtures of diastereomers) and 6, respectively
Scheme 2). These oxindoles were only moderately stable
and were used directly in the next cyclization step.
1
. Synthesis
.1. Tryptamine precursors
An ef®cient synthesis of 3-(3-indolyl)-pyrrolidines has
1
1.2. Pictet±Spengler condensations
The Pictet±Spengler reaction of aldehydes with the secon-
dary amines 1, 3 and 5 did not proceed under standard
conditions such as tri¯uoroacetic acid in CH Cl or re¯ux
1
8
recently been published. Acid catalyzed condensation of
maleimide with indole followed by lithium aluminum
hydride reduction afforded cyclic tryptamine 1 (Scheme
2). Piperidine analog 3 was prepared in two steps by base
catalyzed coupling of N-benzyl-3-piperidone with indole
following a literature procedure.
indolyl)-piperidine 5 was prepared from commercially
available N-benzyl-4-piperidone via the same procedure.
2
2
in benzene. In general, tri¯uoroacetic acid in re¯uxing
ethanol (method A) or in toluene (method B) were most
suitable with respect to the yield and reaction times
(Table 1). To obtain the desired bridged tetrahydro-b-carbo-
lines from acid labile aldehydes such as 5,5-diethoxypen-
tanal, re¯uxing in toluene in the absence of an acid catalyst
and prolonged reaction times were required. Reaction of
pyrrolidine derivative 1 with some representative aldehydes
gave ethano-bridged tetrahydro-b-carbolines 7±10 in
acceptable yields as separable mixtures of diastereomers
(Scheme 3). Depending on the volatility and stability of
the aldehyde, 1.5±15 equiv. of this reagent were used. Little
1
9
2
0±22
The symmetric 4-(3-
A simple and generally applicable method for selective
oxidation of indoles at the 2-position was adapted for the
preparation of oxindoles 2, 4 and 6.
protonated at the 3-position under strongly acidic conditions
i.e. conc. HCl), allowing addition of dimethyl sulfoxide to
2
3,24
The indole ring is
(
Table 1. Pictet±Spengler reactions of amines 1, 3 and 5 with aldehydes as shown in Schemes 3±5
a
b
c
Precursor
Product
R
Ratio a:b
Conditions
Yield
1
1
1
1
3
3
3
3
3
3
5
7
8
9
H
Pentyl
Phenyl
4,4-Diethoxybutyl
H
Ethyl
i-Propyl
Pentyl
Phenyl
4,4-Diethoxybutyl
Pentyl
±
A
B
C
C
A
C
B
C
B
C
B
74
53
58
55
73
54
15
64
58
73
3
45:55
46:54
61:39
±
71:29
50:50
70:30
95:5
67:33
±
10
11
12
13
14
15
16
17
a
1
Ratio according to H NMR spectra of the crude reaction mixtures.
A: EtOH, TFA, re¯ux, 3 h; B: toluene, TFA, re¯ux, 6 h; C: toluene, re¯ux, 9 h.
Isolated yields in % after separation of the diastereomers.
b
c

B. E. A. Burm et al. / Tetrahedron 57 (2001) 2039±2049
2041
Scheme 3. Pictet±Spengler reactions with 3-(3-indolyl)pyrrolidine 1.
Scheme 4. Pictet±Spengler reactions with 3-(3-indolyl)piperidine 3.
preference for one of the diastereomers was observed, as is
shown in Table 1. The structure of pentyl-substituted dia-
stereomer 8a was identi®ed unequivocally by X-ray
membered ring, which is normally formed during the
Pictet±Spengler reaction. A second complication is the
energetically disfavored conformation that the initially
formed iminium salt has to adopt for cyclization.
2
5
analysis. All other isomers in this pyrrolidine series were
1
characterized by comparison of their H NMR spectra.
1
.3. Oxindole spiro-cyclizations
Exposure of piperidine derivative 3 to the reaction con-
ditions described for 1 gave satisfactory results with most
2
6
of the aldehydes. The diastereoselectivity was somewhat
better than in the pyrrolidine series. NOESY experiments
established the cis or trans relationship of the propyl-bridge
relative to the C-1 substituent in the two diastereomers a and
b (Scheme 4). These experiments further showed that the
syn-orientation of the C-1 substituent in isomer a forced the
six-membered ring into a boat conformation, while without
interference of the C-1 substituent the energetically favor-
able chair conformation as in b was adopted.
Condensation reactions of the oxindoles 2, 4 and 6 with
representative aldehydes were investigated using a variety
of both acidic and basic conditions. Pure acetic acid at 908C
or sodium acetate in methanol either at room temperature or
re¯ux proved to be suitable, depending on the aldehyde. In
general the acid catalyzed reactions gave somewhat higher
yields.
Pyrrolidine substituted oxindole 2 was examined ®rst.
Instability of this compound is probably responsible for
the low yields in the condensation reactions (Scheme 6).
In principle four diastereomeric 1-azabicyclo[2.2.1]hep-
tanes can be formed. In the reaction with formaldehyde,
An additional methylene group between the indole nucleus
and the secondary amine in tryptamine analog 5 will result
in the formation of a b-carboline homolog after Pictet±
Spengler condensation. Although a variety of reaction
conditions were applied, merely slow decomposition of
the starting materials was observed. Only from the reaction
with hexanal, which required a large excess of aldehyde and
long reaction times, was a small amount of the bridged
indoloazepine 17 isolated (Scheme 5). The sluggishness of
this condensation can be attributed to the formation of a
seven-membered ring instead of a more favorable six-
Scheme 5. Pictet±Spengler reactions with 4-(3-indolyl)piperidine 5.

2
042
B. E. A. Burm et al. / Tetrahedron 57 (2001) 2039±2049
Scheme 6. spiro-Cyclization reactions.
however, the formation of only one out of two possible
isomers was observed (18, RˆH), whereas in the case of
hexanal and benzaldehyde, respectively, three and two
diastereomers (19, Rˆpentyl and 20, Rˆphenyl; Table 2)
were formed. Low yields in combination with dif®culties
during separation of the isomers prevented complete struc-
tural assignment in this series.
aliphatic aldehydes, longer reaction times and excess of
aldehyde were required to obtain acceptable yields. Out of
four possible diastereomers only the two `ring'-isomers
were formed; for steric reasons the R-substituent obviously
prefers an exo-orientation in relation to the bicyclic ring
system in both isomers, as was deduced from model studies.
During NMR analysis in CDCl it turned out that both
3
Piperidyl substituted oxindole 4 gave better results in the
cyclization reactions. The resulting diastereomeric aza-
bicyclo[3.2.1]octanes 21a,b and 22a,b were separated
using ¯ash chromatography and fully characterized with
pentyl-substituted diastereomers 22a and 22b were con®gu-
rationally unstable, most likely as a result of trace amounts
of acid in the CDCl . After one night at room temperature
3
partial isomerization had taken place and this process could
be completed by heating the NMR sample at 508C for 6 h.
Both pure isomers equilibrated to the same 63:37 isomer
ratio under these conditions, which is exactly the same as
was obtained from their synthesis in acetic acid. No such
observation was made with the formaldehyde derived
products 21. To con®rm the stability of 21a and 21b, both
pure isomers were heated in acetic acid at 908C. No isomer-
ization was observed under these conditions and it took
several hours at 1108C before some isomerization had
taken place. Benzaldehyde was completely unreactive in
the condensation reaction with 4. With large amounts of
reagent and prolonged reaction times the only process
observed was decomposition of the starting material.
2D NMR spectroscopy. The unsubstituted spiro-compound
2
1 (RˆH), obtained by reaction with one equivalent of
formaldehyde, was formed as a 3:1 mixture of the two pos-
sible diastereomers. With hexanal, as an example for
Table 2. spiro-Cyclization reactions of amines 2, 4 and 6 with aldehydes as
shown in Scheme 6
a
b
c
Precursor
Product
R
Ratio a:b
Conditions
Yield
2
2
2
4
4
4
4
6
6
6
6
6
18
19
20
21
22
22
23
24
25
25
26
26
H
1 isomer
3 isomers
69:31
76:24
63:37
55:45
±
A
B
B
A
A
B
A, B
A, B
A
6
8
6
81
57
57
0
d,e
Pentyl
Phenyl
H
Pentyl
Pentyl
Phenyl
H
Pentyl
Pentyl
Phenyl
Phenyl
d
The spiro-cyclization of oxindole 6 with several aldehydes
resulted in the formation of the indolo-quinuclidine (azabi-
cyclo[2.2.2]octane) ring system (Scheme 6). Condensation
of 6 with formaldehyde, which should lead to the parent ring
system in this series, gave no product at all and only un-
identi®ed polymeric material was formed. The use of
hexanal was more successful and the diastereomeric
1-azabicyclo[2.2.2]octanes 25a and 25b were obtained in
reasonable yield after chromatographic separation (the
yields are based on indolopiperidine 5). Due to the
±
0
21:79
36:64
±
47
61
0
B
A
B
d
36:64
22
a
1
Ratio according to H NMR spectra of the crude reaction mixtures.
A: HOAc, 908C; B: NaOAc, MeOH.
Isolated yields in % after separation of the diastereomers.
Inseparable mixture.
b
c
d
e
Ratio 50:5:45.

B. E. A. Burm et al. / Tetrahedron 57 (2001) 2039±2049
2043
symmetry in the quinuclidine ring system only two dia-
stereomers are possible and preference for the sterically
favored diastereomer 25b was observed. In contrast to the
dimethyl sulfoxide (1.5 mL, 20.0 mmol) aqueous hydro-
chloric acid (3.0 mL, 36.4 mmol, 37%) was added drop-
wise. The mixture was stirred during 30 min at rt, then
water and an aqueous sodium bisul®te solution (3 mL)
were added. The mixture was stirred during several minutes,
saturated with K CO and EtOAc/5% EtOH (5 mL) was
1-azabicyclo[3.2.1]octanes 22a and 22b, the separate
isomers 25a and 25b showed no isomerization when
exposed to the same reaction conditions that were used for
their formation. With benzaldehyde a moderate yield of the
two inseparable isomers 26a and 26b was obtained. Structure
analysis of these rigid spiro-structures was easily performed
with NOE spectroscopy, as is shown in Scheme 6.
2
3
added. The layers were separated and the water layer was
extracted with EtOAc/5% EtOH (3£). The combined
organic layers were dried (Na SO ) and evaporated
2
4
affording 4 (585 mg, 1.57 mmol, 79%), as two isomers
1
3
1
according to the C NMR spectrum. H NMR d 7.21±
7.14 (m, 2H, H-6 or H-7), 6.96 (t, Jˆ7.5 Hz, 1H, H-5),
6.84 (d, Jˆ7.5 Hz, 1H, H-4), 3.31 (br s, 1H, H-3), 3.03 (br
d, Jˆ11.8 Hz, 1H, H-9 or H-11 ), 2.97 (br d, Jˆ12.2 Hz,
In summary, we demonstrated that cyclic tryptamine
analogs are suitable precursors for the synthesis of a variety
of new indole derived ring systems. Examples were
presented for all of the six possible ring systems, and the
scope and limitations of these condensation reactions were
established.
eq
eq
1H, H-9 or H-11 ), 2.77±2.68 (m, 1H, H-9 , H-11 ),
eq
eq
ax
ax
2.60 (s, (CH ) SO), 2.51±2.43 (m, 1H), 2.27±2.18 (m,
2
3
1
3
1H), 1.70±1.58 (m, 2H), 1.51±1.39 (m, 1H); C NMR d
1
1
4
49.5 (C-2), 142.5 (C-7a), 128.1 (C-3a), 128.0 (C-3a),
27.6, 127.6, 124.5, 124.1, 121.6, 121.5, 109.5, 109.4,
9.9 (C-3), 49.7 (C-3), 49.5, 48.6, 46.3, 46.2, 40.7
2. Experimental
(
(CH ) SO), 40.2 (C-8), 40.1 (C-8), 26.9 (C-13), 26.7 (C-
3 2
13); IR n 3436, 1706; HRMS (FAB) obs. mass 217.1360,
calcd for C H N O (M11) 217.1341.
2.1. General information
1
3
17
2
All reagents and solvents were used as commercially
available, unless indicated otherwise. Flash chroma-
2
4
.1.3. 4-(2-Oxindol-3-yl)piperidine (6). To a mixture of
-(3-indolyl)piperidine 5 (2.07 g, 10.4 mmol) in dimethyl
2
7
tography refers to puri®cation using the indicated eluents
and Janssen Chimica silica gel 60 (0.030±0.075 mm). Infra-
red (IR) spectra were obtained from CHCl solutions unless
sulfoxide (1.4 mL, 20.0 mmol) hydrochloric acid (5.0 mL,
.61 mol, 37%) was added dropwise. The mixture was
stirred during 45 min at rt, then EtOAc (20 mL), EtOH
1 mL) and a saturated Na CO solution (25 mL) were
0
3
indicated otherwise, using a Bruker IFS 28 FT-spectro-
photometer and wavelengths are reported in cm . Proton
2
1
(
2
3
1
nuclear magnetic resonance ( H NMR) spectra and carbon
added at 08C. The water layer was further basi®ed with
K CO , the layers were separated and the water layer
1
3
nuclear magnetic resonance ( C NMR; APT) spectra were
determined in CDCl3 using a Bruker ARX 400 (400,
2
3
extracted with EtOAc/5% EtOH (3£). The combined
organic layers were dried (Na SO ) and evaporated. The
2
100 MHz, respectively) spectrometer, unless indicated
4
yellow oil thus obtained still contained dimethyl sulfoxide,
but was used for the condensations. An analytical sample
was prepared by ¯ash chromatography (CH Cl /MeOH/
otherwise. Mass spectra and accurate mass measurements
were performed on a JEOL JMS-SX/SX 102 A Tandem
Mass Spectrometer using Fast Atom Bombardment (FAB)
or Electron Impact (EI). A resolving power of 10,000 (10%
valley de®nition) for high-resolution electron impact or
FAB mass spectrometry was used.
2
2
concd NH OH 80:15:5) followed by crystallization from
4
EtOAc, yielding 6 (1.29 g, 5.94 mmol, 57%) as a crystalline
yellow compound: mp 149±1518C; H NMR d 7.22 (d,
1
Jˆ7.5 Hz, 1H, H-4 or H-7), 7.18 (t, Jˆ7.7 Hz, 1H, H-5 or
H-6), 6.98 (t, Jˆ7.5 Hz, 1H, H-5 or H-6), 6.82 (t, Jˆ7.7 Hz,
2
.1.1. 3-(2-Oxindol-3-yl)pyrrolidine (2). To a solution of
1
1
8
1
H. H-4 or H-7), 3.34 (d, Jˆ3.5 Hz, 1H, slow exchange with
eq eq
3-(3-indolyl)pyrrolidine
(106 mg, 0.57 mmol) in
D, H-3), 3.08 (br d, Jˆ12.5 Hz, 1H, H-10 or H-12 ), 3.01
dimethyl sulfoxide (1.5 mL, 21.1 mmol) aqueous hydro-
chloric acid (3.0 mL, 0.37 mol, 37%) was added dropwise.
The mixture was stirred during 45 min at rt, and EtOAc
(
br d, Jˆ12.4 Hz, 1H, H-10 or H-12 ), 2.58 (ddd,
eq
eq
Jˆ12.4 Hz, Jˆ12.4 Hz, Jˆ3.0 Hz, 1H, H-10 or H-12ax),
ax
2
.25±2.18 (m, 2H, H-8, H-10 or H-12 ), 1.67 (br d,
ax ax
(
(
20 mL), EtOH (1 mL) and a saturated Na CO solution
3
25 mL) were added at 08C. The water layer was further
2
Jˆ12.7 Hz, 1H, H-9 or H-13 ), 1.59 (dddd, Jˆ12.4 Hz,
eq
eq
Jˆ12.4 Hz, Jˆ12.4 Hz, Jˆ4.2 Hz, 1H, H-9 or H-13 ),
basi®ed with K CO , the layers were separated and the
3
ax
ax
2
1
.51 (br d, Jˆ13.0 Hz, 1H, H-9 or 13 ), 1.38 (dddd,
ax
water layer extracted with EtOAc/5% EtOH (3£). When a
eq
eq
Jˆ12.4 Hz, Jˆ12.4 Hz, Jˆ12.4 Hz, Jˆ4.2 Hz, 1H, H-9
third, yellow layer was being formed more water and K CO
2
3
or H-13 ); IR n 3436, 1708; HRMS (EI) obs. mass
ax
were added. The combined organic layers were dried
Na SO ) and evaporated giving oxindole 2 together with
dimethyl sulfoxide. Due to its instability the product was not
2
16.1263, calcd for C H N O 216.1263.
13 16 2
(
2
4
1
further puri®ed: H NMR (CDCl /5% CD OD) d 8.59 (br s,
3
2.2. Pictet±Spengler condensations
3
1
H, H-1), 7.23 (d, Jˆ7.8 Hz, 1H, H-4 or H-7), 7.16 (t,
Jˆ7.9 Hz, 1H, H-5 or H-6), 6.99 (t, Jˆ7.8 Hz, 1H, H-5 or
2.2.1. General procedure A. A solution of the amine,
tri¯uoroacetic acid (1 equiv.) and the aldehyde (1.5±
4 equiv.) in EtOH was re¯uxed during 3 h. When formalde-
hyde was used as the aldehyde, methoxyamine hydrochlo-
ride (1.5±4 equiv.) and water (5 mL) were added and
re¯uxing was continued for 2 h. The mixture was concen-
trated in vacuo and EtOAc and a saturated aqueous solution
H-6), 6.84 (d, Jˆ7.8 Hz, 1H, H-4 or H-7), 3.55±3.50 (m,
1
1
H), 3.24±3.07 (m, 1H), 3.03±2.81 (m, 3H), 2.72±2.57 (m,
H), 2.60 (s, (CH ) SO), 1.72±1.58 (m, 1H).
3
2
2
3
.1.2. 3-(2-Oxindol-3-yl)piperidine (4). To a mixture of
1
-(2-indolyl-3-yl)piperidine 3 (400 mg, 2.0 mmol) in
9

2
044
B. E. A. Burm et al. / Tetrahedron 57 (2001) 2039±2049
of Na CO were added. The layers were separated and the
2
Jˆ8.0 Hz, 1H, H-6 or H-9), 7.05 (t, Jˆ7.2 Hz, 1H, H-7 or
H-8), 6.99 (t, Jˆ7.2 Hz, 1H, H-7 or H-7 or H-8), 6.57 (s, 2H,
3
water layer was extracted with EtOAc (3£). The combined
organic layers were dried (Na SO ) and evaporated.
2
CHCO ), 4.11±4.08 (m, 1H, H-1), 3.58±3.51 (m, 1H, H-3),
2
4
3
.51 (br s, 1H, H-5), 3.29 (d, Jˆ10.6 Hz, 1H, H-11), 3.05±
2.2.2. General procedure B. To a solution of the amine and
2.98 (m, 1H, H-3), 2.91 (d, Jˆ10.6 Hz, 1H, H-11), 2.17±
2.08 (m, 1H, H-4), 1.94±1.85 (m, 3H, H-4, H-12), 1.76±
1.72 (m, 1H, H-13), 1.62±1.55 (m, 1H, H-13), 1.40±1.32
(m, 4H, H-14, H-15), 0.92 (t, Jˆ6.7 Hz, 3H, H-16); C
NMR (d -DMSO) d 167.2 (CHCO ), 136.1, 134.7
tri¯uoroacetic acid (1 equiv.) in re¯uxing toluene, the
aldehyde (10 equiv.) was added in portions over a period
of 2 h. The mixture was re¯uxed during 4 h, concentrated in
vacuo and EtOAc and a saturated aqueous solution of
Na CO were added. The layers were separated and the
1
3
6
2
(CHCO ), 124.3, 120.8, 118.6, 117.3, 114.6, 111.2, 65.1
2
2
3
water layer was extracted with EtOAc (3£). The combined
(C-1), 53.9 (C-3 or C-11), 52.5 (C-3 or C-11), 35.4, 34.2,
31.2 (C-5), 25.7, 22.0, 13.9 (H-16); IR n 3436; HRMS (EI)
obs. mass 268.1945, calcd for C H N 268.1939.
organic layers were dried (Na SO ) and evaporated.
4
2
1
8
24
2
2
.2.3. General procedure C. To a solution of the amine in
2
2.2.6. Crystallographic data of 8a. Monoclinic, P2 /c,
5
re¯uxing toluene, the aldehyde (10 equiv.) was added over a
period of 2 h. The mixture was re¯uxed during another 7 h,
cooled to rt and concentrated in vacuo.
1
Ê
aˆ9.6605(9), bˆ15.995(2), cˆ10.291(2) A, bˆ99.20(2)8,
3
23
Ê
Vˆ1569.7(5) A , Zˆ4, D ˆ1.14 g cm , l(CuKa)ˆ
x
2
1
Ê
1
.5418 A, m(CuKa)ˆ5.0 cm , F(000)ˆ584, room
2
(
2
.2.4. Pictet±Spengler reaction of 1 with formaldehyde
7). General procedure A was followed using 1 (500 mg,
.16 mmol), tri¯uoroacetic acid (210 mL, 2.16 mmol),
temperature. Final Rˆ0.067 for 2113 observed re¯ections.
2.2.7. Pictet±Spengler reaction of 1 with benzaldehyde
(9a and 9b). General procedure C was followed using 1
(981 mg, 5.27 mmol) and 1 benzaldehyde (1.85 mL,
18.2 mmol). According to a H NMR spectrum of the
crude mixture the diastereomers had been formed in a
ratio of 9a/9bˆ46:54 and were separated by ¯ash
chromatography (PE/EtOAc 50:50 then PE/EtOAc/NEt3
60:30:10). Both 9a (382 g, 1.39 mmol, 26%) and 9b
(463 mg, 1.68 mmol, 32%) were obtained from EtOAc as
crystals.
formalin (450 mL, 5.85 mmol, 36%) and methoxyamine
hydrochloride (450 mg, 5.38 mmol). Crystallization from
EtOAc gave 7 (403 mg, 2.0 mmol, 74%): mp 262±2638C
(
1
2408C subl.); H NMR d 7.96 (br s, 1H, H-10), 7.55±7.52
(
m, 1H, H-6 or H-9), 7.30±7.27 (m, 1H, H-6 or H-9), 7.14±
7
.08 (m, 2H, H-7, H-8), 4.47 (d, Jˆ16.7 Hz, 1H, H-1) 3.74
(
(
(
2
d, Jˆ16.7 Hz, 1H, H-1), 3.38±3.36 (m, 1H, H-5), 3.33
ddd, Jˆ12.6 Hz, Jˆ10.0 Hz, Jˆ3.6 Hz, 1H, H-3), 3.08
dt, Jˆ10.8 Hz, Jˆ2.8 Hz, Jˆ2.8 Hz, 1H, H-11), 2.88±
1
3
.80 (m, 1H, H-3), 2.14±2.00 (m, 2H, H-4); C NMR d
1
9a: mp 225±2288C; H NMR d 7.97 (br s, 1H, H-10), 7.61±
136.1 (C-9a), 129.1, 125.4, 121.0 (C-7 or C-8), 119.2 (C-7
or C-8), 117.9, 117.3 (C-6), 110.8 (C-9), 58.5 (C-11), 56.3
7.58 (m, 1H, H-6), 7.38±7.35 (m, 5H, Ar±H), 7.24±7.22 (m,
1H, H-9), 7.15±7.11 (m, 2H, H-7, H-8), 5.68 (br s, 1H, H-1),
3.43 (br s, 1H, H-5), 3.31 (dd, Jˆ10.7 Hz, Jˆ2.7 Hz, 1H,
H-11), 2.99±2.93 (m, 1H, H-3), 2.70±2.63 (m, 1H, H-3),
2.04±2.01 (m, 2H, H-4); IR n 3436; HRMS (EI) obs. mass
274.1464, calcd for C H N 274.1470.
(C-1) 54.0 (C-3), 37.4 (C-4), 31.2 (C-5); IR n 3435; HRMS
(EI) obs. mass 198.1142, calcd for C H N 198.1157.
1
3
14
2
2.2.5. Pictet±Spengler reaction of 1 with hexanal (8a and
8b). General procedure B was followed using 1 (1.01 g,
5.43 mmol), tri¯uoroacetic acid (415 mL, 5.39 mmol) and
1
9
18
2
1
1
9b: mp 214±2158C (1708C subl.); H NMR (CD OD) d 7.54
hexanal (3.22 mL, 26.9 mmol). According to H NMR
spectroscopy of the crude mixture the diastereomers had
been formed in a ratio of 8a/8bˆ45:55 and were separated
by ¯ash chromatography (PE/EtOAc 50:50 then PE/EtOAc/
3
(d, Jˆ7.0 Hz, 1H, H-6 or H-9), 7.39±7.30 (m, 3H Ar±H),
7.25±7.23 (m, 3H, H-6 or H-9, Ar±H), 7.08±7.00 (m, 2H,
H-7, H-8), 5.04 (s, 1H, H-1), 3.52±3.50 (m, 1H, H-5), 3.43
(ddd, Jˆ12.6 Hz, Jˆ10.0 Hz, Jˆ3.6 Hz, 1H, H-3), 3.30±
3.27 (m, 1H, H-11), 3.17±3.10 (m, 1H, H-3), 2.54 (dd,
Jˆ11.0 Hz, Jˆ2.9 Hz, 1H, H-11), 2.18±2.10 (m, 2H,
NEt 60:30:10). Both isomers were obtained as colorless
3
crystals: 8a (326 mg, 1.21 mmol, 22%) from EtOAc and
8b (651 mg, 1.69 mmol, 31%) from EtOH as its 1:1 salt
with fumaric acid.
1
3
H-4); C NMR (CD OD) d 138.3, 135.4, 134.4, 133.3,
3
1
32.0, 131.7, 126.2, 124.9, 122.4, 120.9, 114.7, 112.0,
1
a: mp 151±1528C; H NMR d 7.72 (br s, 1H, H-10), 7.52
8
(
72.6 (C-1), 57.7 (C-3 or C-11), 55.4 (C-3 or C-11), 40.3
(C-4), 35.7 (C-5); IR n 3436; HRMS (EI) obs. mass
274.1465, calcd for C H N 274.1470.
d, Jˆ6.5 Hz, 1H, H-6 or H-9), 7.30 (d, Jˆ6.8 Hz, 1H, H-6
or H-9), 7.14±7.07 (m, 2H, H-7, H-8), 4.39 (dd, Jˆ9.7 Hz,
Jˆ4.8 Hz, 1H, H-1), 3.32 (br s, 1H, H-5), 3.20 (d,
Jˆ10.7 Hz, 1H, H-11), 3.10±3.03 (m, 2H, H-11, H-3),
1
9
18
2
2.2.8. Pictet±Spengler reaction of 1 with 5,5-diethoxy-
pentanal (10a and 10b). General procedure C was followed
using 1 (36 mg, 0.19 mmol) and 5,5-diethoxypentanal
2
1
1
1
1
3
.98±2.92 (m, 1H, H-3), 2.00±1.92 (m, 2H, H-4), 1.81±
.68 (m, 3H, H-12, H-14), 1.60±1.52 (m, 1H, H-12),
.46±1.38 (m, 4H, H-13, H-15), 0.95 (t, Jˆ7.0 Hz, 3H, H-
1
(348 mg, 2.0 mmol). According to a H NMR spectrum of
1
3
6); C NMR d 135.7 (C-9a), 133.5 (C-5b), 125.3 (C-1a),
21.0, 119.4, 117.5, 116.7 (C-5a), 110.7, 62.4 (C-1), 60.6, 44.4,
5.8, 32.0 (C-5), 32.0, 31.8, 26.2, 22.5, 14.0 (C-16); IR n 3436;
the crude reaction mixture the diastereomers had been
formed in a ratio of 10a/10bˆ61:39. Separation by ¯ash
chromatography (PE/EtOAc 50:50 then PE/EtOAc/NEt3
70:15:5) gave 10a (23 mg, 0.07 mmol, 35%) and 10b
HRMS (EI) obs. mass 268.1927, calcd for C H N 268.1939.
24
18
2
(
13 mg, 0.04 mmol, 20%) as an oil.
1
b: mp 151±1528C; H NMR (d -DMSO) d 10.90 (s, 1H,
H-10), 7.50 (d, Jˆ7.7 Hz, 1H, H-6 or H-9), 7.31 (d,
8
6
1
10a: H NMR d 8.05 (br s, 1H, H-10), 7.51 (d, Jˆ7.3 Hz,

B. E. A. Burm et al. / Tetrahedron 57 (2001) 2039±2049
2045
1
according to H NMR spectroscopy of the crude mixture:
H NMR (representative parts of the spectrum) d 8.06 (br s,
11 HH ,, HH -- 17 1) .), 7.69 (d, Jˆ7.8 Hz, 1H H-7), 7.62 (d, Jˆ7.8 Hz,
1
7
4
3
H, H-6 or H-9), 7.29 (d, Jˆ7.3 Hz, 1H, H-6 or H-9) 7.12±
.07 (m, 2H, H-7, H-8), 4.58 (t, Jˆ5.5 Hz, 1H, H-15), 4.49±
.41 (m, 1H, H-1), 3.74±3.62 (m, 2H, OCH CH ), 3.60±
1
2
3
.47 (m, 2H OCH CH ), 3.35 (br s, 1H, H-5), 3.22 (d,
2
3
Jˆ10.6 Hz, 1H. H-11), 2.71 (dd, Jˆ10.6 Hz, Jˆ2.7 Hz,
1
H, H-11), 3.05±2.97 (m, 2H, H-3), 2.02±1.56 (m, 8H,
2.2.12. Pictet±Spengler reaction of 3 with hexanal (14a
and 14b). General procedure C was followed using 3
(40 mg, 0.20 mmol) and hexanal (340 mL, 2.82 mmol).
Flash chromatography (EtOAc/PE/NEt 65:30:5) yielded
3
14a (26.0 mg, 0.09 mmol, 46%) and 14b (10 mg,
0.04 mmol, 18%), both as yellow oils.
H-4, H-12, H-13, H-14), 1.24 (t, Jˆ7.1 Hz, 3H,
OCH CH ), 1.24 (t, Jˆ7.1 Hz, 3H, OCH CH ), 1.23 (t,
2
3
2
3
Jˆ7.1 Hz, 3H, OCH CH ); IR n 3436.
2
3
1
1
1
7
3
3
2
8
0b: H NMR d 8.08 (br s, 1H, H-10), 7.53 (d, Jˆ7.3 Hz,
H, H-6 or H-9), 7.28 (d, Jˆ7.3 Hz, 1H, H-6 or H-9) 7.14±
.06 (m, 2H, H-7, H-8), 4.56 (t, Jˆ5.1 Hz, 1H, H-15), 3.74±
.34 (m, 6H, H-1, H-3, OCH CH ), 3.34 (br s, 1H, H-5),
1
14a: H NMR d 7.94 (br s, 1H, H-11), 7.46 (d, Jˆ7.1 Hz,
1H, H-7), 7.33 (d, Jˆ7.3 Hz, 1H, H-10), 7.17±7.06 (m, 2H,
H-8, H-9), 4.33±4.28 (dd, Jˆ6.6 Hz, Jˆ4.3 Hz, 1H, H-1),
3.41±3.37 (m, 1H, H-12), 3.24±3.13 (m, 3H, H-3, H-12),
3.05 (br s, 1H, H-6), 1.97±1.08 (m, 12H, H-4, H-5, H-13,
H-14, H-15, H-16), 0.97 (t, Jˆ6.8 Hz, 3H, H-17); IR n
2
3
.17 (d, Jˆ11.0 Hz, 1H, H-11), 2.83±2.76 (m, 1H, H-3),
.71 (dd, Jˆ11.0 Hz, Jˆ2.7 Hz, 1H, H-11), 2.00±1.62 (m,
H, H-4, H-12, H-13, H-14), 1.25 (t, Jˆ7.1 Hz, 3H,
OCH CH ), 1.24 (t, Jˆ7.1 Hz, 3H, OCH CH ); IR n 3436.
2
3
2
3
3
435.
2
(
0
.2.9. Pictet±Spengler reaction of 3 with formaldehyde
11). General procedure A was followed using 3 (40 mg,
.20 mmol), tri¯uoroacetic acid (19 mL, 0.20 mmol), para-
1
14b: H NMR d 7.89 (br s, 1H, H-11), 7.49 (d, Jˆ7.2 Hz,
1H, H-7), 7.34 (d, Jˆ7.0 Hz, 1H, H-10), 7.19±7.03 (m, 2H,
H-8, H-9), 3.79±3.76 (m, 1H, H-1), 3.25±3.12 (m, 3H, H-3,
H-6, H-12), 3.10±2.96 (m, 2H, H-3, H-12), 1.91±1.18 (m,
11H, H-4, H-5, H-13, H-14, H-15, H-16), 1.16±1.11 (m, 1H,
H-4), 0.98±0.79 (m, 3H, H-17); IR n 3436.
formaldehyde (9 mg, 0.30 mmol), EtOH (2 mL) and
methoxyamine hydrochloride (41 mg, 0.50 mmol). Crystal-
lization from EtOAc/PE gave 11 (31 mg, 0.15 mmol, 73%):
1
mp 231±2348C; H NMR d 8.17 (br s, 1H, H-11), 7.49 (d,
Jˆ7.5 Hz, 1H, H-7 or H-10), 7.33 (d, Jˆ7.8 Hz, 1H, H-7 or
H-10), 7.17±7.09 (m, 2H, H-8, H-9), 4.44 (d, Jˆ17.2 Hz,
2.2.13. Pictet±Spengler reaction of 3 with benzaldehyde
(15a and 15b). General procedure B was followed using 3
(32 mg, 0.16 mmol), benzaldehyde (205 mL, 2.01 mmol)
and tri¯uoroacetic acid (12 mL, 0.16 mmol). The dia-
stereomers were formed in a ratio of 15a/15bˆ95:5 as indi-
1
H, H-1), 3.78 (d, Jˆ17.2 Hz, 1H, H-1), 3.24 (br d, 1H,
Jˆ13.2 Hz, H-12), 3.15 (ddd, Jˆ13.7 Hz, Jˆ13.7 Hz,
Jˆ3.8 Hz, 1H, H-3), 3.07±3.01 (m, 3H, H-3, H-6, H-12),
1
.91±1.87 (m, 2H, H-5), 1.58±1.47 (m, 1H, H-4), 1.20 (br d,
1
3
1
Jˆ13.7 Hz, 1H, H-4); C NMR (CDCl /5% CD OD) d
cated by H NMR spectroscopy of the crude reaction
3
3
1
1
36.0 (C-10a), 133.5 (C-6b), 126.0 (C-11a), 120.8 (C-7),
18.8 (C-9), 117.2 (C-8) 111.9 (C-6a), 110.7 (C-10), 55.1
mixture. From this mixture only 15a (38 mg, 0.09 mmol,
58%) was isolated as a solid.
(
2
2
C-1 or C-12), 53.0 (C-1 or C-12), 49.4 (C-3), 28.1 (C-4),
1
15a: mp 208±2098C; H NMR d 7.90 (br s, 1H, H-11), 7.55
5.8 (C-6), 18.3 (C-5); IR n 3436; HRMS (EI) obs. mass
12.1315, calcd for C H N 212.1313.
(d, Jˆ7.3 Hz, 1H, H-7), 7.47±7.36 (m, 5H, Ar±H), 7.29 (d,
Jˆ7.4 Hz, 1H, H-10), 7.18±7.11 (m, 2H, H-8, H-9), 5.56 (s,
1H, H-1), 3.44 (d, Jˆ12.6 Hz, 1H, H-12), 3.32 (d, Jˆ
12.6 Hz, 1H, H-12), 3.14 (br s, 1H, H-6), 2.70 (dt, Jˆ
14.0 Hz, Jˆ3.5 Hz, 1H, H-3), 2.56±2.50 (m, 1H, H-3),
1.96±1.92 (m, 2H, H-5), 1.60±1.54 (m, 1H, H-4), 1.10±
1
4
16
2
2
.2.10. Pictet±Spengler reaction of 3 with propionalde-
hyde (12a and 12b). General procedure C was followed.
Using 3 (50 mg, 0.25 mmol) and propionaldehyde (270 mL,
3
(32.2 mg, 0.13 mmol, 54%) in a ratio of 12a/12bˆ71:29
according to H NMR spectroscopy: H NMR (from the
mixture) d 7.94 (br s, 1H, H-11),7.88 (br s, 1H, H-11),
7
H-10), 7.17±7.06 (m, 4H, H-8, H-9), 4.24±4.18 (m, 1H,
H-1), 3.97±3.88 (m, 1H, H-1), 3.41±3.37 (m, 1H, H-12),
.75 mmol) yielded an inseparable mixture of diastereomers
1
3
1.07 (m, 1H, H-4); C NMR (CD OD) d 138.2 (C-11a),
3
1
1
137.3 (C-6b), 135.2 (C-10), 130.9, 128.4, 128.0, 126.9,
121.3, 119.4, 118.0, 114.1, 110.9, 63.8 (C-1), 56.2 (C-12),
48.0 (C-3), 28.9 (C-4), 27.5 (C-6), 19.9 (C-5); IR n 3436;
HRMS (EI) obs. mass 288.1622, calcd for C H N
2
.46 (d, Jˆ7.1 Hz, 2H, H-7), 7.33 (d, Jˆ7.3 Hz, 2H,
2
0
20
288.1626.
3
.24±3.13 (m, 6H, H-3, H-6, H-12), 1.99±1.24 (m, 6H, H-4,
1
H-5, H-13), 0.97 (t, Jˆ6.8 Hz, 3H, H-14), 0.93 (t, Jˆ6.8 Hz,
15b: H NMR d 5.92 (s, 1H, H-6), 4.06 (d, Jˆ12.6 Hz, 1H,
H-12), 3.72 (d, Jˆ12.6 Hz, 1H, H-12); the other signals
could not be discerned from the crude reaction mixture.
1
3
3H, H-14); C NMR (from the mixture) d 138.0, 136.2,
135.8, 126.5, 126.0, 121.9, 121.2, 120.1, 119.2, 119.1,
117.7, 113.0, 111.1, 110.6, 60.7 (C-1), 60.2 (C-12), 56.2
(
2
(
C-12), 53.7 (C-3), 49.8 (C-3), 33.4 (C-6), 30.9, 28.7,
8.2, 26.3 (C-6), 25.1, 19.3, 18.6, 11.9 (C-14), 11.6
C-14); IR n 3436.
2.2.14. Pictet±Spengler reaction of 3 with 5,5-diethoxy-
pentanal (16a and 16b). General procedure C was followed
using 3 (300 mg, 1.50 mmol) and 5,5-diethoxypentanal
(3.71 g, 21.3 mmol). Flash chromatography (EtOAc/PE/
NEt 65:30:5) yielded 16a (258 mg, 0.72 mmol, 48%) and
16b (132 mg, 0.38 mmol, 25%), both as yellow oils.
2
.2.11. Pictet±Spengler reaction of 3 with iso-butyralde-
3
hyde (13a and 13b). General procedure B was followed.
Using 3 (50 mg, 25 mmol) and iso-butyraldehyde (180 mL,
1
2.0 mmol) yielded an inseparable mixture of diastereomers
16a: H NMR d 7.99 (br s, 1H, H-11), 7.46 (d, Jˆ7.6 Hz,
(
9.7 mg, 0.04 mmol, 15%) in a ratio of 13a/13bˆ50:50
1H, H-7), 7.33 (d, Jˆ6.5 Hz, 1H, H-10), 7.15±7.06 (m, 2H,

2
046
B. E. A. Burm et al. / Tetrahedron 57 (2001) 2039±2049
H-8, H-9), 4.59±4.48 (m, 1H, H-16), 4.31±4.27 (m, 1H,
H-1), 3.73±3.60 (m, 2H, OCH CH ), 3.57±3.48 (m, 2H,
rated. Flash chromatography afforded the pure diastereo-
mers.
2
3
OCH CH ), 3.37 (d, Jˆ11.3 Hz, 1H, H-12), 3.19±3.14 (m,
2
3
2
H, H-3, H-12), 3.04 (br s, 1H, H-6), 2.91 (dt, Jˆ14.0 Hz,
2.3.2. General procedure B. The oxindole was prepared
prior to use from the corresponding amine according to
the procedure described above. To a solution of this freshly
prepared oxindole and NaOAc in MeOH, aldehyde (5 equiv.
based on the indole precursor) was added. The reaction
mixture was stirred during the time and temperature indi-
cated and concentrated in vacuo. An aqueous saturated solu-
tion of K CO and diethyl ether were added. The layers were
Jˆ3.7 Hz, 1H, H-3), 1.96±1.76 (m, 8H, H-5, H-13, H-14,
H-15), 1.42±1.36 (m, 1H, H-4), 1.35±1.16 (m, 7H, H-4,
OCH CH ); C NMR d 138.3 (C-10a), 135.5 (C-6b),
1
3
2
3
1
1
26.2 (C-11a), 120.9 (C-8), 119.1 (C-7), 117.5 (C-9),
12.1 (C-6a), 110.6 (C-10), 102.5 (C-16), 61.2
(
OCH CH ), 60.7 (OCH CH ), 57.1 (C-1), 55.6 (C-12),
2 3 2 3
4
6
2
6.7 (C-3), 33.3 (C-15), 30.4 (C-13), 28.6 (C-14), 26.4 (C-
), 21.8 (C-5), 19.0 (C-4), 15.1 (OCH CH ); IR n 3492,
360, 1458; HRMS (FAB) obs. mass 357.2543, calcd for
2
3
separated and the water layer was extracted with diethyl
ether (3£). The combined organic layers were washed
with H O, dried (Na SO ) and evaporated. Flash chromato-
2
3
C H N O (M11) 357.2542.
2
2
33
2
2
2
2
4
graphy gave the pure diastereomers.
1
1
1
6b: H NMR d 8.04 (br s, 1H, H-11), 7.47 (d, Jˆ7.6 Hz,
H, H-7), 7.33 (d, Jˆ7.9 Hz, 1H, H-10), 7.15±7.05 (m, 2H,
2.3.3. Condensation of 2 with formaldehyde (18). General
procedure A was followed with 2 freshly prepared from 1
(100 mg, 0.54 mmol) and paraformaldehyde (16 mg,
0.54 mmol) in acetic acid (2 mL). The reaction mixture
was stirred during 2 h at 908C. Flash chromatography
(CH Cl /MeOH/conc. NH OH 80:20:2) afforded 18 (7 mg,
H-8, H-9), 5.54±4.46 (m, 1H, H-16), 3.69±3.60 (m, 3H,
H-1, OCH CH ), 3.55±3.44 (m, 2H, OCH CH ), 3.11 (dt,
2
3
2
3
Jˆ14.4 Hz, Jˆ3.8 Hz, 1H, H-3), 3.10±3.08 (m, 2H, H-6,
H-12), 2.97±2.95 (m, 2H, H-3, H-12), 1.89±1.44 (m, 8H,
H-5, H-13, H-14, H-15), 1.39±1.35 (m, 1H, H-4), 1.27±1.11
2
2
4
1
1
3
(
(
(
(
4
(
m, 7H, H-4, OCH CH ); C NMR d 137.9 (C-10a), 135.7
3
0.03 mmol, 6%) as a glass: H NMR d 8.04 (br s, 1H, H-11),
7.53 (d, Jˆ6.8 Hz, 1H, H-7), 7.30 (d, Jˆ7.6 Hz, 1H, H-8 or
H-9), 7.15±7.08 (m, 1H, H-8, H-9), 4.49 (d, Jˆ16.6 Hz, 1H,
H-1), 3.77 (d, Jˆ16.6 Hz, 1H, H-1), 3.40±3.32 (m, 2H, H-
3a, H-5), 3.09 (d, Jˆ10.8 Hz, 1H, H-13a), 2.93 (dd, Jˆ
10.8 Hz, Jˆ2.8 Hz, 1H, H-13), 2.88±2.81 (m, 1H, H-3 or
H-4a), 2.14±2.01 (m, 2H, H-3 or H-4a, H-4); IR n 3435,
1705.
2
C-6b), 126.3 (C-11a), 121.1 (C-8), 119.2 (C-7), 117.7
C-9), 112.2 (C-6a), 110.7 (C-10), 102.6 (C-16), 61.3
OCH CH ), 60.8 (OCH CH ), 57.2 (C-1), 55.8 (C-12),
2
3
2
3
6.9 (C-3), 33.5 (C-15), 30.5 (C-4), 28.8 (C-13), 26.5
C-6), 21.9 (C-14), 19.2 (C-5), 15.3 (OCH CH ); IR n
2 3
3492, 2360, 1458; HRMS (FAB) obs. mass 357.2559,
calcd for C H N O (M11) 357.2542.
2
2
33
2
2
2
.2.15. Pictet±Spengler reaction of 5 with hexanal (17).
General procedure B was followed. To a solution of 5
300 mg, 1.50 mmol) and tri¯uoroacetic acid (120 mL,
2.3.4. Condensation of 2 with hexanal (19). General pro-
cedure B was followed using 2 freshly prepared from 1
(400 mg, 1.98 mmol) and hexanal (1.2 mL, 10 mmol). The
mixture was stirred at rt during one night. In the crude
reaction mixture three isomers could be discerned in a
ratio of 50:5:45. Flash chromatography (EtOAc/PE/NEt3
60:40:10) gave 19a (23 mg, 0.08 mmol, 4%) and an insepa-
rable mixture of 19b and 19c (25 mg, 0.09 mmol, 4.5%).
(
1
3
.56 mmol) in toluene (10 mL), hexanal (3.60 mL,
0.0 mmol) was added in portions over a period of 5 days.
Flash chromatography (PE/EtOAc 50:50 then PE/EtOAc/
NEt 60:30:10) yielded 17 (12 mg, 0.04 mmol, 2.7%) as a
3
1
yellow oil: H NMR d 8.07 (br s, 1H, H-10), 7.48 (d,
Jˆ7.0 Hz, 1H, H-6 or H-9), 7.30 (d, Jˆ7.1 Hz, 1H, H-6
or H-9), 7.14±7.07 (m, 2H, H-7, H-8), 4.28±4.22 (m, 1H,
H-1), 3.49±3.42 (m, 1H), 3.28 (br s, 1H, H-5), 3.23±3.16
1
19a: H NMR d 8.64 (br s, 1H, H-11), 7.35 (d, Jˆ7.6 Hz,
1H, H-7), 7.20 (t, Jˆ7.6 Hz, 1H, H-8 or H-9), 7.00 (t,
Jˆ7.6 Hz, 1H, H-8 or H-9), 6.89 (d, Jˆ7.6 Hz, 1H, H-10),
3.37 (br d, Jˆ9.9 Hz, 1H, H-13), 3.08±2.92 (m, 3H, H-1,
H-3), 2.59±2.56 (m, 2H, H-5, H-13), 2.47±2.42 (m, 1H),
1.56±1.47 (m, 1H), 1.40±1.27 (m, 3H), 1.25±1.00 (m, 4H),
0.91 (m, 1H), 0.72 (t, Jˆ6.9 Hz, 3H, H-18); C NMR d
181.2 (C-12), 140.3 (C-11a), 131.8 (C-7a), 127.6, 124.5,
121.8, 109.4 (C-11), 76.8 (C-1), 59.9, 59.0, 54.9, 50.0
(
(
(
(
(
m, 1H), 3.10±2.96 (m, 2H), 2.06±1.88 (m, 4H), 1.87±1.75
m, 2H), 1.68±1.62 (m, 1H), 1.59±1.46 (m, 1H), 1.43±1.35
m, 4H), 0.97±0.87 (m, 3H, H-17); C NMR d 187.2
C-10a), 135.8 (C-9a), 126.3 (C-5b), 121.0 (C-8), 119.1
C-7), 119.0 (C-5a), 117.3 (C-6), 110.5 (C-9), 64.1 (C-1),
1
3
1
3
48.5, 40.0, 33.9, 31.9, 30.6, 29.2, 26.5, 24.3 (C-5), 22.5. 14.0
(
C-17); IR n 3437.
(
3
C-5), 33.3, 31.5, 27.2, 23.0, 22.3, 13.8 (C-18); IR n
436, 1703.
2.3. spiro-Cyclization reactions
1
9b: H NMR (from the mixture) d 9.10 (br s, 1H, H-11),
1
2
.3.1. General procedure A. The oxindole was freshly
7.22±7.15 (m, 2H, H-7, H-8 or H-9), 6.99 (t, Jˆ7.6 Hz, 1H,
H-8 or H-9), 6.92 (d, Jˆ7.6 Hz, 1H, H-10), 3.79 (br d,
Jˆ9.4 Hz, 1H, H-13), 3.42±3.38 (m. 1H, H-1), 3.10±3.03
(m, 1H), 2.89±2.82 (m, 1H), 2.67±2.66 (m, 1H, H-5), 2.62±
2.53 (m, 2H, H-13), 1.65±1.60 (m, 1H), 1.49±1.41 (m, 1H),
1.30±1.00 (m, 6H), 0.91±0.87 (m, 1H), 0.70 (t, Jˆ6.9 Hz,
prepared from the corresponding amine according to the
procedure described above prior to use. A solution of
oxindole and aldehyde (1±5 equiv. based on the indole
precursor) in acetic acid was stirred during the time and
temperature indicated. The reaction mixture was concen-
trated in vacuo, then EtOAc and an aqueous saturated solu-
tion of K CO were added. The layers were separated and
1
3
3H, H-18); C NMR d 182.9 (C-12), 141.8 (C-11a), 128.2
(C-7a), 127.5, 126.9, 120.9, 109.9 (C-11), 71.0 (C-1), 59.9,
56.1, 54.9, 50.8 (C-5), 43.9, 31.4, 26.8, 25.4, 22.1, 13.7
(C-18); IR n 3436, 1703.
2
3
the water layer was extracted with EtOAc (3£). The
combined organic layers were dried (Na SO ) and evapo-
2
4

B. E. A. Burm et al. / Tetrahedron 57 (2001) 2039±2049
2047
1
9c: H NMR (from the mixture) d 8.02 (br s, 1H, H-11),
1
1
7
21b: H NMR d 9.16 (br s, 1H, H-12), 7.60 (d, Jˆ7.5 Hz,
1H, H-8), 7.20 (t, Jˆ7.5 Hz, 1H, H-10), 7.00 (t, Jˆ7.5 Hz,
1H, H-9), 6.90 (d, Jˆ7.5 Hz, 1H, H-11), 4.09 (br d, Jˆ
11.4 Hz, H-14 ), 3.56 (d, Jˆ13.0 Hz, 1H, H-1 ), 3.18±
.35 (d, Jˆ7.6 Hz, 1H, H-7), 7.21 (d, Jˆ7.6 Hz, 1H, H-8 or
H-9), 7.00 (t, Jˆ7.6 Hz, 1H, H-8 or H-9), 6.87 (d, Jˆ7.6 Hz,
1
3
2
H, H-10), 3.37 (br d, Jˆ9.8 Hz, 1H, H-13), 3.08±2.96 (m,
H, H-1, H-3, H-13), 2.58±2.56 (m, 2H, H-3, H-5), 2.47±
.41 (m, 1H), 1.63±0.98 (m, 7H), 0.94±0.75 (m, 2H), 0.73
eq
endo
3.01 (m, 3H, H-3, H-1 ), 2.87 (d, Jˆ11.4 Hz, 1H, H-14 ),
exo
ax
2.61 (s, (CH ) SO), 2.43±2.34 (m, 1H, H-4 ), 2.17 (br s,
3
2
ax
(
t, Jˆ7.0 Hz, H-18); IR n 3436, 1703.
1H, H-6), 1.94±1.85 (m, 2H, H-5), 1.60±1.55 (m, 1H,
1
3
H-4eq); C NMR d 183.4 (C-13), 141.7 (C-11a), 130.3
(C-7a), 127.9 (C-10), 124.5 (C-8), 121.8 (C-9), 109.8
(C-11), 59.5, 59.2, 58.2, 55.5, 44.5 (C-6), 40.8 ((CH ) SO)
2
.3.5. Condensation of 2 with benzaldehyde (20). General
procedure B was followed using 2 freshly prepared from 1
149 mg, 0.80 mmol) and benzaldehyde (120 mL,
3
2
(
26.9 (C-5), 18.2 (C-4); IR n 3436, 1709; HRMS (EI) obs.
mass 229.1345, calcd for C H N O (M11) 229.1341.
1
5
2
.20 mmol). The mixture was stirred during one night at
58C. The diastereomers were formed in a ratio of
1
4
17
2
1
0a:20bˆ69:31 according to H NMR spectroscopy. Flash
2.3.7. Condensation of 4 with hexanal (22). General pro-
cedure A was followed using 4 prepared from 3 (20 mg,
0.1 mmol) and hexanal (60 mL, 0.5 mmol). After stirring
chromatography (PE/EtOAc 50:50 then PE/EtOAc/NEt3
60:25:15) gave an inseparable mixture of the two isomers
2
0a and 20b (14 mg, 0.005 mmol, 6%).
during 5 h at 908C, a mixture of two diastereomers in a
1
ratio of 22a/22bˆ63:37 was formed according to
H
1
0a: H NMR (from the mixture) d 7.95 (br s, 1H, H-11),
.47±6.93 (m, 8H, H-7, H-8, H-9, Ar±H), 6.83 (d,
2
7
NMR spectroscopy of the crude reaction mixture (see
text). Alternatively the reaction could be performed follow-
ing general procedure B, reacting 4 (55 mg, 0.15 mmol),
NaOAc (20 mg, 0.25 mmol) and hexanal (60 mL,
Jˆ7.5 Hz, 1H, H-10), 4.23 (br s, 1H, H-1), 4.19 (br d,
Jˆ9.8 Hz, 1H, H-13), 3.31 (td, Jˆ12.1 Hz, Jˆ12.1 Hz,
Jˆ4.6 Hz, 1H, H-3a), 3.04±2.99 (m, 1H, H-3), 2.80 (d,
Jˆ4.1 Hz, 1H, H-5), 2.74±2.68 (m, 1H, H-13), 2.19±2.12
1
0.5 mmol) during 6 h at 558C. According to H NMR spec-
troscopy of the crude reaction mixture two diastereomers in
a ratio of 22a/22bˆ55:45 had been formed. Flash chroma-
tography (EtOAc/PE/NEt3 65:30:5) gave 22a (14 mg,
0.05 mmol, 31%) and 22b (12 mg, 0.04 mmol 26%), both
as a glass.
1
3
(
m 1H, H-4a), 1.74±1.65 (m, 1H, H-4b); C NMR (from the
mixture) d 178.9 (C-12), 141±109 (24 C's), 77.7 (C-1), 61.1
C-3), 60.9 (C-6), 54.7 (C-3), 51.7 (C-5), 23.6 (C-4); IR n
(
3437, 1705.
1
0b: H NMR (from the mixture) d 8.12 (br s, 1H, H-11),
.47±6.93 (m, 5H, H-7, H-8 or H-9, Ar±H), 6.56 (t,
1
2
7
22a: H NMR d 7.86 (br s, 1H, H-12), 7.36 (d, Jˆ7.6 Hz,
1H, H-8), 7.19 (t, Jˆ7.6 Hz, H-10), 6.97 (t, Jˆ7.6 Hz, 1H,
H-9), 6.85 (d, Jˆ7.6 Hz, 1H, H-11), 3.67±3.62 (m, 2H, H-1,
H-14 ), 3.20±3.09 (m, 2H, H-3), 3.04±2.93 (m, 2H, H-4 ,
Jˆ7.6 Hz, 1H, H-8 or H-9), 6.39 (d, Jˆ7.6 Hz, 1H, H-10),
4
.45 (br s, 1H, H-1), 3.49 (br d, Jˆ9.9 Hz, 1H, H-13), 3.17
eq
ax
(
(
td, Jˆ11.3 Hz, Jˆ11.3 Hz, Jˆ4.4 Hz, 1H, H-3), 3.06±3.04
H-14 ), 2.21 (br d, Jˆ2.9 Hz, 1H, H-6), 2.06±2.01 (m, 1H,
ax
m, 1H,H-3), 2.74±2.68 (m, 2H, H-5, H-13), 2.59±2.53 (m,
H-5), 1.86±1.77 (m, 1H, H-5), 1.52±1.44 (m, 1H, H-15),
1.43±1.36 (m, 1H, H-4 ), 1.34±1.23 (m, 2H, H-17), 1.18±
0.99 (m, 4H, H-16, H-18) 0.98±0.86 (m, 1H, H-15), 0.76 (t,
1
H, H-4), 1.49±1.46 (m, 1H, H-4); C NMR (from the
3
1
eq
mixture) d 178.9 (C-12), 141±109 (24C), 79.4 (C-1), 61.0
C-3), 60.2 (C-6), 55.3 (C-3), 50.9 (C-5), 25.0 (C-4); IR n
1
3
(
Jˆ6.7 Hz, 3H, H-19); C NMR d 180.1 (C-13), 139.5
3437, 1705.
(C-11a), 132.5 (C-7a), 127.5 (C-10), 124.3 (C-8), 121.8
C-9), 109.1 (C-11), 71.1 (C-1), 62.6 (C-7), 60.7 (C-14),
(
2
2
.3.6. Condensation of 4 with formaldehyde (21a and
1b). General procedure A was followed using 4 prepared
56.9 (C-3), 49.0 (C-6), 34.5 (C-15), 31.6 (C-16), 27.4
(C-5), 27.4 (C-17), 22.3 (C-18), 17.8 (C-4) 13.8 (C-19);
IR n 3437, 1708; HRMS (EI) obs. mass 298.2031, calcd
for C H N O 298.2045.
from 3 (67 mg, 0.36 mmol) and paraformaldehyde (11 mg,
.37 mmol). After 2 h at 908C the conversion was complete.
0
1
9
26
2
1
According to the H NMR spectrum of the crude reaction
mixture two diastereomers in a ratio of 76:24 had been
formed. Flash chromatography (EtOAc/EtOH/NEt3
75:15:10) gave 21b (21 mg, 0.07 mmol, 19%) as a glass.
The other diastereomer 21a (50 mg, 0.22 mmol, 62%) was
crystallized from acetonitrile.
1
22b: H NMR d 7.84 (br s, 1H, H-12), 7.61 (d, Jˆ7.6 Hz,
1H, H-8), 7.23 (t, Jˆ7.6 Hz, 1H, H-10), 7.05 (t, Jˆ7.6 Hz,
1H, H-9), 6.87 (d, Jˆ7.6 Hz, 1H, H-11), 4.26 (br d, Jˆ
11.6 Hz, 1H, H-14 ), 3.37±3.34 (m 1H, H-1), 3.04±2.93
eq
(m, 1H, H-3 ), (m 1H, H-3 ), 2.83 (dd, Jˆ11.6 Hz,
ax
eq
Jˆ1.5 Hz, 1H, H-14 ), 2.43±2.32 (m, 1H, H-4 ), 2.21 (br
ax
ax
1
1a: mp 177±1798C; H NMR d 9.65 (br s, 1H, H-12), 7.32
2
s, 1H, H-6), 1.97±1.92 (m, 2H, H-5), 1.80±1.72 (m, 1H,
H-15), 1.62±1.51 (m, 1H, H-4 ), 1.38±1.02 (m, 7H,
(
(
(
1
d, Jˆ7.5 Hz, 1H, H-8), 7.16 (t, Jˆ7.5 Hz, 1H, H-10), 6.95
t, Jˆ7.5 Hz, 1H, H-9), 6.83 (d, Jˆ7.5 Hz, 1H, H-11), 3.56
br d, Jˆ13.1 Hz, 2H, H-1 , H-14 ), 3.38 (d, Jˆ13.1 Hz,
eq
1
3
H-15, H-16, H-18), 0.77 (t, Jˆ6.8 Hz, 3H, H-19);
C
NMR d 180.1 (C-13), 140.7 (C-11a), 131.1 (C-7a), 127.7
(C-10), 124.5 (C-8), 122.0 (C-9), 109.2 (C-11), 72.5(C-1),
62.5 (C-7), 59.1 (C-14), 56.6 (C-3), 45.6 (C-6), 33.0 (C-15),
31.7 (C-16), 28.0 (C-17), 26.5 (C-5), 22.5 (C-18), 18.6
(C-4), 13.8 (C-19); IR n 3437, 1708; HRMS (EI) obs,
mass 298.2031, calcd for C H N O 298.2045.
endo
eq
H, H-1 ), 3.29±2.98 (m, 4H, H-3, H-4 , H-14 ), 2.17 (br
exo ax ax
s, 1H, H-6), 2.06±1.97 (m, 1H, H-5), 1.84±1.75 (m, 1H,
H-5), 1.38±1.33 (m, 1H, H-4eq); C NMR d 181.1
1
3
(
(
C-13), 139.8 (C-11a), 136.6 (C-7a), 127.6 (C-10), 122.6
C-8), 122.0 (C-9), 109.1 (C-11), 61.2 (C-1), 60.8 (C-7),
1
9
26
2
5
(
2
8.5 (C-3 or C-14), 56.0 (C-3 or C-14), 48.1 (C-6), 27.9
C-5), 17.4 (C-4); IR n 3437, 1708; HRMS (EI) obs. mass
28.1259, calcd for C H N O 228.1263.
2.3.8. Condensation of 6 with hexanal (25a and 25b).
General procedure B was followed using 6 prepared from
1
4
16
2

2
048
B. E. A. Burm et al. / Tetrahedron 57 (2001) 2039±2049
5 (400 mg, 2.0 mmol), NaOAc (492 mg, 6.0 mmol) and
hexanal (1.25 mL, 10.0 mmol). Stirring the reaction mixture
H-1a), 3.75±3.70 (m, 1H, H-13a), 3.48±3.30 (m, 4H, H-3a,
H-3b), 3.23±3.04 (m, 4H, H-13a, H-13b), 2.88±2.80 (m,
1H, H-14b), 2.35±2.30 (m, 2H, H-14a, H-4a), 2.02±1.92
(m, 1H, H-14b), 1.82 (br s, 2H, H-5a, H-5b), 1.64±1.58
(m, 1H, H-4a), 1.57±1.41 (m, 3H, H-14a, H-4b, H-14b);
during 10 h at 658C resulted in complete conversion.
According to the H NMR spectrum of the crude mixture
the diastereomers had been formed in a ratio of 25a/
1
1
3
25bˆ36:64. Flash chromatography (EtOAc/PE/NEt3
60:40:10) yielded both diastereomers 25a (131 mg,
0.44 mmol, 22%) and 25b (232 mg, 0.78 mmol, 39%) as a
C NMR d 183.1 (C-12), 180.1 (C-12), 140.7, 140.6,
140.5, 139.2, 135.2, 130.3, 129.4, 129.1, 128.0, 127.9,
127.8, 127.4, 127.0, 126.6, 126.3, 126.2, 125.8, 125.3,
123.8, 121.8, 121.1, 115.5, 110.2, 110.0, 65.2 (C-1), 63.6
(C-6), 55.1 (C-6), 55.0 (C-6), 49.5, 49.3, 43.1 (2C), 31.9
(C-5), 31.6 (C-5), 22.8, 22.7, 22.3, 20.7; IR n 3435, 1705.
glass. Alternatively the reaction could be performed follow-
ing general procedure A. Using 6 (20 mg, 0.1 mmol) and
hexanal (25 mL, 0.2 mmol), after stirring during 8 h at 908C,
the diastereomers 25a/25b (14 mg, 0.05 mmol, 47%) were
1
formed in a ratio of 21:79 according to the H NMR spec-
trum of the crude reaction mixture.
Acknowledgements
1
2
1
1
5a: H NMR d 8.30 (br s, 1H, H-11), 7.37 (d, Jˆ7.4 Hz,
H, H-7), 7.19 (t, Jˆ7.4 Hz, 1H, H-9), 7.03 (t, Jˆ7.4 Hz,
H, H-8), 6.86 (d, Jˆ7.4 Hz, 1H, H-10), 3.45±3.37 (m, 1H,
We wish to thank J. Fraanje, K. Goubitz and H. Schenk of
this University for the X-ray crystal structure determination
of compound 8a.
H-13), 3.21±3.16 (m, 1H, H-3 ), 3.15±3.05 (m, 3H, H-1,
ar
H-3), 2.81 (dd, Jˆ11.0 Hz, Jˆ12.2 Hz, 1H, H-13), 2.49±
2
1
.41 (m, 1H, H-14), 2.18±2.10 (m, 1H, H-4 ) 1.85±1.77 (m,
ar
References
H, H-15a), 1.71 (br s, 1H, H-5), 1.52±1.44 (m, 2H, H-4,
H-15), 1.35±1.27 (m, 1H, H-14), 1.19±1.01 (m, 5H, H-16,
H-17, H-18), 0.98±0.88 (m, 1H, H-16), 0.72 (t, Jˆ6.8 Hz,
1. Agarwal, A.; Pearson, P. P.; Taylor, E. W.; Li, H. B.;
Dahlgren, T.; Hersl oÈ f, M.; Yang, Y.; Lambert, G.; Nelson,
D. L.; Regan, J. W.; Martin, A. R. J. Med. Chem. 1993, 36,
4006 (and references cited therein).
1
H, H-19); C NMR d 179.7 (C-12), 140.3 (C-10a), 134.9
3
3
(
C-6a), 127.4 (C-7), 124.2 (C-8), 121.6 (C-9), 109.2 (C-10),
6
3
4.4 (C-1), 52.6 (C-6), 49.7 (C-3), 41.4 (C-13), 31.5 (C-16),
1.4 (C-5), 29.7 (C-15), 26.5 (C-17), 22.9 (C-4), 22.3
2. King, F. D.; Brown, A. M.; Gaster, L. M.; Kaumann, A. J.;
Medhurst, A. D.; Parker, S. G.; Parsons, A. A.; Patch, T. L.;
Raval, P. J. Med. Chem. 1993, 36, 1918.
(
(
C-18), 21.8 (C-14), 13.8 (C-19); IR n 3436, 1702; HRMS
FAB) obs. mass 299.2117, calcd for C H ON (M11)
1
9
27
2
3. Macor, J. E.; Olgilvie, R. J.; Wythes, M. J. Tetrahedron Lett.
1996, 37, 4289.
299.2123.
4
. Ezquerra, J.; Pedregal, C.; Lamas, C.; Pastor, A.; Alvarez, P.;
Vaquero, J. J. Tetrahedron Lett. 1996, 37, 683.
1
2
1
1
1
5b: H NMR d 7.88 (br s, 1H, H-11), 7.37 (d, Jˆ7.6 Hz,
H, H-7), 7.22 (t, Jˆ7.6 Hz, 1H, H-9), 7.02 (t, Jˆ7.6 Hz,
H, H-8), 6.91 (d, Jˆ7.6 Hz, 1H, H-10), 3.32 (t, Jˆ7.3 Hz,
H, H-1), 3.27±3.20 (m, 2H, H-3, H-13), 3.03±2.94 (m, 2H,
5. Audia, J. E.; Evrard, D. A.; Murdoch, G. R.; Droste, J. J.;
Nissen, J. S.; Schenck, K. W.; Fludzinski, P.; Luciates, V. L.;
Nelson, D. L.; Cohen, M. L. J. Med. Chem. 1996, 39, 2773.
6. Kawashima, Y.; Horiguchi, A.; Taguchi, M.; Tuyuki, Y.;
Karasawa, Y.; Araki, H.; Hatayama, K. Chem. Pharm. Bull.
1995, 43, 783.
H-3, H-13), 2.66±2.63 (m, 1H, H-14 ), 2.06±2.00 (m, 1H,
a
H-4 ), 1.69 (br s, 1H, H-5), 1.59±1.52 (m, 1H, H-15), 1.50±
ar
.43 (m, 1H, H-14b), 1.39±1.30 (m, 3H, H-4, H-15, H-17),
.10±0.82 (m, 4H, H-16, H-17, H-18), 0.72±0.65 (m, 4H,
H-16, H-19); C NMR d 181.8 (C-12), 140.6 (C-10a),
1
1
7. Street, L. J.; Baker, R.; Book, T.; Kneen, C. O.; MacLeod,
A. M.; Merchant, K. J.; Showell, G. A.; Saunders, J.; Herbert,
R. H.; Freedman, S. B.; Harley, E. A. J. Med. Chem. 1990, 33,
2690.
1
3
1
1
29.6 (C-6a), 127.6 (C-8 or C-9), 126.6 (C-7 or C-10),
21.3 (C-7 or C-10), 109.9 (C-8 or C-9), 61.9 (C-1), 53.3
(
C-6), 49.2 (C-3 or C-13), 41.6 (C-3 or C-13), 31.3 (C-18),
8. Nilsson, B. M.; Sundquist, S.; Johansson, G.; Nordvall, G.;
Glas, G.; Nilvebrant, L.; Hacksell, U. J. Med. Chem. 1995,
38, 473.
3
2
1
2
1.1 (C-5), 30.4 (C-15), 25.8 (C-16), 22.6 (C-4 or C-14),
2.1 (C-17), 20.4 (C-4 or C-14), 13.7 (C-19); IR n 3435,
704; HRMS (EI) obs. mass 298.2059, calcd for C H N O
1
9
26
2
9. Johansson, G.; Sundquist, S.; Nordvall, G.; Nilsson, B. M.;
Brisander, M.; Nilvebrant, L.; Hacksell, U. J. Med. Chem.
98.2045.
1
997, 40, 3804.
2
2
.3.9. Condensation of 6 with benzaldehyde (26a and
6b). General procedure B was followed using 6 freshly
10. Swain, C. J.; Baker, R.; Kneen, C.; Herbert, R.; Moseley, J.;
Seward, E. M.; Stevenson, G. I.; Beer, M.; Stanton, J.;
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prepared from 5 (200 mg, 1.0 mmol), NaOAc (246 mg,
.0 mmol) and benzaldehyde (0.51 mL, 5.0 mmol). The
reaction did not go to completion (44 h, 60±658C). Accord-
3
1
ing to the H NMR spectrum of the crude mixture two
diastereomers had been formed in a ratio of 26a/26bˆ
12. Pictet, A.; Spengler, T. Ber. 1911, 44, 2030.
13. See, for a review on the Pictet±Spengler condensation: Cox,
E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
36:64. Flash chromatography (EtOAc/PE/NEt 40:55:5)
yielded an inseparable mixture of two diastereomers 26a/
3
1
2
(
1
6b (78 mg, 0.26 mmol, 22%) as a glass: H NMR d 9.40
br s, 1H, H-11b), 9.28 (br s, 1H, H-11a), 7.55 (d, Jˆ7.4 Hz,
H, H-7a), 7.29±6.77 (m, 15H, Ar±Ha, Ar±Hb, H-8a, H-9a,
14. Bailey, P. D.; Hollinshead, S. P.; Moore, M. H.; Morgan,
K. M.; Smith, D. I.; Vernon, J. M. Tetrahedron Lett. 1994,
35, 3587.
H-10a, H-7b, H-9b), 6.65 (t, Jˆ7.4 Hz, 1H, H-8b), 6.57 (d,
15. Ban, Y.; Taga, N.; Oishi, T. Tetrahedron Lett. 1974, 187.
16. Oishi, T.; Nagai, M.; Ban, Y. Tetrahedron Lett. 1968, 491.
Jˆ7.4 Hz, 1H, H-10b), 4.86 (br s, 1H, H-1b) 4.64 (br s, 1H,

B. E. A. Burm et al. / Tetrahedron 57 (2001) 2039±2049
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25. Crystallographic data have been deposited at the CCDC, 12
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1