Microwave accelerated Pictet-Spengler reactions of tryptophan with ketones directed toward the preparation of 1,1-disubstituted indole alkaloids

Article abstract of DOI:10.1016/j.tet.2004.10.025

Using the Pictet-Spengler reactions of tryptophan with aldehydes under acidic conditions at ambient temperature, diastereoisomers of 1,3-disubstituted-1,2,3,4-tetrahydro-β-carbolines could readily be furnished in short time (0.5-4 h) with good to excellent yields (50-98%). Though intrinsically slow in reaction rates, ketone reactions can be accelerated (from days to minutes) using microwaves in open vessels with high isolated yields (67-99%), making those carbolines feasible reaction intermediates for the synthesis of both natural and unnatural indole alkaloids. Preparation of two indole alkaloids, tetrahydro-β-carbolinediketopiperazines and tetrahydro-β-carbolinehydantoins, were briefly discussed. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.10.025

Tetrahedron 60 (2004) 12075–12084
Microwave accelerated Pictet–Spengler reactions of tryptophan
with ketones directed toward the preparation of 1,1-disubstituted
indole alkaloids
*
Fu-Ming Kuo, Ming-Chung Tseng, Ya-Hew Yen and Yen-Ho Chu
Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 621, Taiwan, ROC
Received 7 June 2004; revised 8 October 2004; accepted 12 October 2004
Available online 27 October 2004
Abstract—Using the Pictet–Spengler reactions of tryptophan with aldehydes under acidic conditions at ambient temperature,
diastereoisomers of 1,3-disubstituted-1,2,3,4-tetrahydro-b-carbolines could readily be furnished in short time (0.5–4 h) with good to
excellent yields (50–98%). Though intrinsically slow in reaction rates, ketone reactions can be accelerated (from days to minutes) using
microwaves in open vessels with high isolated yields (67–99%), making those carbolines feasible reaction intermediates for the synthesis of
both natural and unnatural indole alkaloids. Preparation of two indole alkaloids, tetrahydro-b-carbolinediketopiperazines and tetrahydro-b-
carbolinehydantoins, were briefly discussed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
literature, most results either required long reaction times or
were with low reaction yields. Only few gave satisfactory
results.2,3 Owing to its intrinsically slow reaction, the
development of rapid and convenient methods would
therefore be of value to speed up the optimization process
of the ketone reactions. Of these, microwaves can offer its
great potential in expediting synthetic organic reactions.4
We report here that the Pictet–Spengler reaction of
tryptophan 1 with ketones 2 by microwaves proceeds
readily to produce 1,1-disubstituted tetrahydro-b-carbolines
3 in much shorter reaction times with good to excellent
isolated yields (Scheme 1). Most significantly, this micro-
wave-accelerated Pictet–Spengler reaction is clean and the
tetrahydro-b-carboline adducts are only products under our
experimental conditions.
Since its discovery, the Pictet–Spengler reaction has been
extensively studied and continues to be a focus of research
in areas including the preparation of new heterocycles for
combinatorial applications and its incorporation in total
synthesis of natural and unnatural products.1 For example,
Katzenellenbogen recently reported a vinylogous Pictet–
Spengler cyclization as the key step aiming to prepare breast
tumor imaging agents.2 Though broadly useful, a vast of the
literature concerning the Pictet–Spengler reactions so far
were most with aldehydes or activated ketones such as 1,2-
dicarbonyl compounds. The reactions with ketones were,
however, known to be either far less reactive at room
temperature (typical reaction time in days) or sluggish under
reflux conditions. Some arylketones even do not react at all
with, for example, tryptophan and consequently these
ketone reactions have seldom been addressed.3
2. Results and discussion
The Pictet–Spengler reaction is an acid-catalyzed intra-
molecular cyclization of the intermediate imine of trypto-
phan, formed by condensation with a carbonyl compound,
to give 1,2,3,4-tetrahydro-b-carbolines 3.1 In our early
investigation of this reaction,3c,5e we utilized a conventional
Pictet–Spengler synthetic protocol of refluxing the trypto-
phan and the carbonyl compound in a solvent such as
toluene to speed up the reaction. We found that, although
aldehydes cyclized readily, ketones often gave product
mixtures contaminated with the failed-to-cyclize imine
intermediates and other side-products of unknown
The low reactivity from ketones may be attributed to, at
first, the slow imine formation and thus a sterically
sensitive, if not totally prohibited, cyclization of the
resulting imine to produce a congested tetrasubstituted
C-1 carbon of the tetrahydro-b-carbolines or tetrahydro-
isoquinolines. For ketone reactions previously reported in
Keywords: Microwave-mediated organic synthesis; Pictet–Spengler reac-
tion; Indole alkaloid.
* Corresponding author. Tel.: C886 5 2428148; fax: C886 5 2721965;
e-mail: cheyhc@ccu.edu.tw
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.025

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F.-M. Kuo et al. / Tetrahedron 60 (2004) 12075–12084
Scheme 1. The Pictet–Spengler reaction.
structures. Only upon extended heating at lower tempera-
ture, we were able to obtain clean reaction with good
product yield. We thus turned our attention to alternative
means known to accelerate organic reactions. We, and
others, have recently reported that microwaves readily
facilitated the Pictet–Spengler reaction of tryptophan with
both aliphatic and aryl aldehydes.5 For example, under our
previously established experimental condition, tryptophan
completed the Pictet–Spengler reaction with benzaldehyde
in toluene within only 15 s with an 83% isolated yield.5e In
this paper, we demonstrate that ketone reactions with
tryptophan could also be effectively accelerated using
microwaves.
in the carbon spectrum than the analogous carbons of the
corresponding cis-isomer, due to the 1,3-interactions
present in the trans-isomer. Using benzaldehyde and
p-tolualdehyde as representative examples, reactions from
aromatic aldehydes were often completed in 3–4 h with high
isolated yields (entries 7 and 8, compounds 3g and 3h). With
L-tryptophan, acyclic ketones at ambient temperature slowly
underwent the Pictet–Spengler reaction and eventually
produced the corresponding adducts with excellent yields
(entries 9 and 10, compounds 3i and 3j). The reactions of the
cyclic ketones, cyclohexanone and cyclopentanone, yielded
the corresponding 1,1-spirocycloalkylated tetrahydro-b-
carbolines with exceedingly different rates (entries 11 and
12, compounds 3k–3l). This result suggested that the Pictet–
Spengler cyclization, as anticipated, is sensitive to the steric
congestion.3j Moreover, reactions of D-tryptophan with
aldehydes or ketones expectedly gave similar, if not
identical, results in reaction time, yield, and product
diastereoisomeric ratio (data not shown in Table 1, but
provided in Section 4).
As shown in Table 1 for the reactions with L-tryptophan,
ketones give the slowest reaction rates at ambient
temperature (13 h–76.5 days, entries 9–12, compounds
3i–3l) and all aliphatic aldehydes studied complete the
Pictet–Spengler reaction in 1 h (entries 1–6, compounds
3a–3f) using 4 equiv of carbonyl compounds. Although they
were significantly different in reaction rates, both ketones
and aldehydes were furnished with good to excellent yields
(50–98%). Except for acetaldehyde, aliphatic aldehydes
with enolizable protons, in general, tended to produce less
Pictet–Spengler adducts, presumably due to competitive
aldol reactions under experimental conditions (50–68%,
entries 2–6, compounds 3b–3f). In all aldehyde cases, the
carboline products were isolated as mixtures of diastereo-
isomers. The assignment for cis/trans-tetrahydro-b-carbo-
lines was based on a detailed study of the 13C NMR
spectroscopy well-established by Cook.1 Thus, the signals
for C-1 and C-3 in the trans-isomer appeared at higher field
Because the slow ketone reactions presented in Table 1 were
totally impractical for use in the library preparation of
1,1-disubstituted natural and unnatural products, we sub-
sequently decided to employ large excess (12 equiv) of
inexpensive and readily available ketones to further
expedite the Pictet–Spengler reactions. Besides it can
shorten the reaction time, the employment of excessive
ketone may also compensate for competitive side reactions
such as aldol condendsation with the aim that low reactivity
of ketone will not plaque the reaction. We were pleased
to find that at ambient temperature the rates of the
Table 1. Synthesis of tetrahydro-b-carbolines from aldehydes and ketones with L-tryptophan at ambient temperaturea
Entry
Product
R1COR2
Tryptophanb
Reaction time
Yield (%)c
Diastereomeric ratiod
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
Acetaldehyde
L-form
L-form
L-form
L-form
L-form
L-form
L-form
L-form
L-form
L-form
L-form
L-form
30 min
1 h
1 h
1 h
1 h
40 min
3 h
4 h
93
68
51
58
50
56
95
78
87
88
84
74f
53:47
50:50
50:50
50:50
42:58
27:73
61:39
62:38
58:42
—
Propionaldehyde
Butyraldehyde
Valeraldehyde
Capronaldehyde
Phenylacetaldehyde
Benzaldehyde
p-Tolualdehyde
2-Butanone
9
16.5 days
76.5 days
13 h
10
11
12
3j
3k
3l
3-Pentanone
Cyclohexanone
Cyclopentanone
—
—
15.5 dayse
a The reaction condition: tryptophan, 255 mg (1.25 mmol); aldehyde or ketone, 5.0 mmol; TFA, 10% (v/v); dichloromethane, 12.5 mL.
b Tryptophan of both forms were used in this study. Only results from L-tryptophan were shown in the table. Results of D-tryptophan were provided in Section 4.
c Isolated yield unless otherwise mentioned. The tetrahydro-b-carbolines were only products.
d The stereochemistry of the diastereomers obtained from aldehyde reaction was readily determined by 13C NMR developed by Cook (Ref. 1). For the given
pair of diastereomers derived from aldehyde reaction, the second number represents the trans isomer in this table and its diastereomeric ratio was measured by
C18-HPLC. In a pair of diastereomers derived from 2-butanone reaction, the second number was arbitrarily assigned as the trans isomer in this table.
e Time required to completely consume the starting tryptophan.
f
Analytical yield. The Pictet–Spengler adduct was contaminated with the failed-to-cyclize imine intermediate.

F.-M. Kuo et al. / Tetrahedron 60 (2004) 12075–12084
Table 2. Cyclization of L-tryptophan with ketones at ambient temperaturea
12077
Entry
Product
R1COR2
[L-Tryptophan]/[R1COR2]
1:4
Yieldb
(%)
1:12
Yieldb
(%)
Reaction time
Diastereomeric
ratioc
Reaction time
Diastereomeric
ratioc
1
2
3
4
5
6
3m
3i
3n
3j
3k
3l
Acetophenone
2-Butanonee
3-Methyl-2-butanone
3-Pentanonee
Cyclohexanone
Cyclopentanone
116 days
16.5 days
58 days
76.5 days
13 h
85d
87
99
88
84
74 g
23:77
58:42
56:44
—
—
—
40 days
2.5 days
12.5 days
5.5 days
3.5 h
62
93f
99
99
89
89
22:78
47:53
67:32
—
—
—
15.5 days
1 day
a The reaction condition: tryptophan, 255 mg (1.25 mmol); ketone, 5.0 mmol; (4 equiv) or 15.0 mmol (12 equiv); TFA, 10% (v/v); dichloromethane, 12.5 mL.
b Isolated yield unless otherwise mentioned. The tetrahydro-b-carbolines were only products.
c The diastereomeric ratio was measured by C18-HPLC. In a pair of diastereomers, the second number was arbitrarily assigned as the trans isomer in this table.
d The degree of reaction conversion. The tetrahydro-b-carbolines were only products and the progress of the reaction was analysis by C18-HPLC.
e Under the conditions of neat TFA or 50% TFA, the progress of the Pictet–Spengler reaction was negligible: 2-butanone in neat TFA, 2% reaction conversion
was detected after 4.5 days; 2-butanone in 50% TFA, only 5% conversion was monitored after 7.5 days; 3-pentanone in neat TFA, 5% reaction conversion
was measured after 16.5 days.
f
In case of [L-tryptophan]/[2-butanone]Z1:8, quantitative yield was isolated after 4.5 days.
g Analytical yield. The Pictet–Spengler adduct was contaminated with the failed-to-cyclize imine intermediate.
Pictet–Spengler reactions with ketones were indeed
improved (Table 2). Results presented in Table 2 clearly
show that all ketones studied completed the Pictet–Spengler
reactions not only in shorter reaction times but also with
better yields. Most significantly, cyclopentanone did not
complete its reaction after 15.5 days when employing
4 equiv of ketone, but using 12 equiv of ketone the reaction
was complete in 1 day with an 89% isolated yield (entry 6 in
Table 2). These results set the stage for ultimate improve-
ment of the Pictet–Spengler reactions of tryptophan with
ketones by microwaves.
(60 8C and 150 W), cyclic ketones such as cyclohexanone
and cyclopentanone reacted cleanly with tryptophan to yield
the corresponding spiro-fused tetrahydro-b-carbolines in 10
and 20 min, respectively, with quantitative isolated yields.
Both cyclohexanone and cyclopentanone reactions if carried
out at ambient temperature required, however, much longer
reaction times (6 h and 2.5 days, respectively) with less
yields (Table 3). Since the Pictet–Spengler reaction is
sensitive to steric hindrance at the site of cyclization, among
acyclic ketones investigated 2-butanone gave the fastest rate
(20 min using microwaves) and 3-methyl-2-butanone was
far less reactive (15 h by microwaves) as expected (entry 2
vs entry 3 in Table 3, compound 3i vs compound 3n). The
preparation of the tetrahydro-b-carboline obtained from
acetophenone reaction with tryptophan deserves additional
comment (compound 3m in Table 3). Using HPLC to
monitor the progress of the acetophenone reaction, we
found that it gave an incomplete reaction even after 49 days
at ambient temperature (Table 3). When we attempted to
shorten the reaction time by increasing the temperature, we
observed that, in our case, harsh conditions such as
conventional reflux or microwaves at higher temperatures
(e.g., 100 8C) gave complete conversion of the starting
tryptophan to produce, however, complicated and degraded
Using large excess of ketones in toluene, we utilized
microwaves to accelerate the synthesis of 1,1-disubstituted
tetrahydro-b-carbolines and were pleased to find that in the
presence of microwaves the Pictet–Spengler reaction
proceeds remarkably well and cleanly with both aliphatic
and aromatic ketones, though the latter are much less
reactive. The details of the investigation are given in
Table 3. Under our experimental conditions, the micro-
waves-accelerated Pictet–Spengler reaction appears to
conduct superior with cyclic ketones than acyclic ketones
(entries 5 and 6 in Table 3, compounds 3k and 3l).
Specifically, under the condition of microwave irradiation
Table 3. Microwave-accelerated Pictet–Spengler reaction of L-tryptophan with ketonesa
Entry
Product
R1COR2
Room temperature
Heated at 60 8Cb
Microwavesc
Reaction
time
Yieldd
(%)
dre
Reaction
time
Yieldd
(%)
dre
Reaction
time
Yieldd
(%)
dre
1
2
3
4
5
6
3m
3i
3n
3j
3k
3l
Acetophenone
2-Butanone
49 daysf
18 h
3-Methyl-2-butanone 11.5 days
90f
74
87
96
68
95
20:80
51:49
68:32
—
—
—
95 h
96
99
86
99
99
99
25:75
55:45
60:40
—
—
—
40 h
67
96
76
91
99
99
23:77
50:50
55:45
—
—
—
3.5 h
62 h
52 h
75 min
55 min
20 min
15 h
3.3 h
10 min
20 min
3-Pentanone
Cyclohexanone
Cyclopentanone
5.5 days
6 h
2.5 days
a The reaction condition: L-tryptophan, 51 mg (0.25 mmol); ketone, 3.0 mmol; (12 equiv); TFA, 10% (v/v); toluene, 2.5 mL.
b The reaction was carried out using a conventional heating device with temperature controlled at 60 8C.
c The microwave-assisted Pictet–Spengler reaction was carried out in an open vessel and temperature-controlled at 60 8C using a commercial instrument
(300 W, Synthewave 402, Prolabo). A 50% microwave power was applied throughout the reaction period to avoid formation of side products of unknown
structures.
d Isolated yield unless otherwise mentioned. The tetrahydro-b-carbolines were only products.
e The diastereomeric ratio (dr) was measured by C18-HPLC. In a pair of diastereomers, the second number was arbitrarily assigned as the trans isomer in this
table.
f
The Pictet–Spengler reaction was incomplete under the experimental condition. The number indicated its percentage of reaction conversion after 49 days.

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F.-M. Kuo et al. / Tetrahedron 60 (2004) 12075–12084
reaction mixtures. Under our optimized and milder
condition (60 8C and 150 W), we were pleased that, despite
an extended reaction time, microwave irradiation at lower
temperature could achieve clean tetrahydro-b-carboline
product with acceptable isolated yield (67%) (entry 1 in
Table 3). Instead of toluene solvent used in this work, we
also employed dimethylformamide, an efficient coupler of
microwaves, for the microwave-assisted reaction and found
that it took a rather longer time to carry out the desired
Pictet–Spengler reaction; for example, only 38% conver-
sion, instead of quantitative conversion in toluene, was
observed if the microwave-mediated tryptophan reaction
with 2-butanone was carried out at 100 8C for 15 min.
Moreover, Table 3 shows that, although the heating with
temperature controlled at the same 60 8C using standard
laboratory setups undoubtedly facilitated the progress of the
Pictet–Spengler reaction, the microwave heating is
evidently far better than conventional heating in terms of
reaction acceleration. This rate enhancement by micro-
waves is likely due to the fact that microwaves transfer heat
efficiently.4 Our results presented in Table 3 clearly
demonstrate that the presence of microwaves greatly
improves the rate of chemical reactions, which can be
critical to high throughput library synthesis, not only with a
large reduction of reaction time (mostly days at ambient
temperature down to hours or even minutes under
microwaves) but also with improvement of, in our case,
the final yield.
overall yields were achieved for compounds 5a–c (50–70%)
via a two-step synthesis: the Pictet–Spengler reaction and
the subsequent hydantoin-forming reaction (Scheme 2).
Using ‘microwaves in organic synthesis’, we are currently
conducting the combinatorial preparation of the ketone-
based tetrahydro-b-carbolinediketopiperazines 4 as well as
tetrahydro-b-carbolinehydantoins 5. These classes of
compounds may possess valuable biological activities.
3. Conclusion
In this investigation, we demonstrate that the slow Pictet–
Spengler condensation of tryptophan with ketones can be
smoothly and cleanly accelerated using microwaves.
Because of the rigid heterocyclic skeleton of the 1,1-
disubstituted tetrahydro-b-carboline pharmacophore and the
vast Pictet–Spengler cyclization literature, our results
reported here present an initially impractical but now
feasible opportunity for further chemical manipulation of
conformationally constrained peptidomimetics, as well as
combinatorial preparation of natural and unnatural indole
alkaloids.
4. Experimental
4.1. General experimental section
To further demonstrate the usefulness of 1,1-disubstituted
tetrahydro-b-carbolines 3 and application of this microwave
methodology toward the preparation of natural and
unnatural indole alkaloids, we carried out the multistep
synthesis of new, ketone-derived demethoxyfumitremorgin
C analog 4 and tetrahydro-b-carbolinehydantoins 5a–c
(Scheme 2). Without attempting to optimize reaction
conditions and isolated yields, our preliminary result
indicated that both classes of compounds can be prepared
from 1,1-disubstituted tetrahydro-b-carbolines 3. For
example, starting from L-tryptophan methyl ester, an overall
isolated yield of 11% for compound 4 via a three-step
synthesis (the Pictet–Spengler reaction, the Schotten–
Baumann acylation, and the deprotection and intramolecular
cyclization) was obtained (Scheme 2). In addition, good
Flash chromatography was performed on silica gel (230–
400 mesh). TLC was carried out on aluminum-backed silica
plates precoated with silica (0.2 mm), which were devel-
oped using standard visualizing agents such as UV
fluorescence and ninhydrin. Analytical HPLC was per-
formed on an Agilent 1100 series equipped with a diode
array detector, using
a C18 column (ChemcoPak
Chemcosorb 5-ODS-H, 5 mm, 4.6!250 mm, flow rate:
1.0 mL/min). Eluant solvent system: (i) 0–10 min; water,
(ii) 10–40 min; acetonitrile/water (0:100 to 100:0) eluant
linear gradient over 30 min, then (iii) 40–50 min; 100%
acetonitrile for additional 10 min, both solvents contain
0.1% TFA. Compound purity and the cis/trans diastereo-
isomeric ratio were measured from integrated peak areas of
HPLC chromatographs generated at 280 nm. Unless
Scheme 2. The preparation of demethoxyfumitremorgin C analog 4 and tetrahydro-b-carbolinehydantoins 5a–c.

F.-M. Kuo et al. / Tetrahedron 60 (2004) 12075–12084
12079
otherwise indicated, all reactions were carried out without
the aid of dry nitrogen or argon. NMR spectra were recorded
on a Bruker AVANCE DPX 400 at 400 MHz (1H) in D2O
and 100.6 MHz (13C) in DMSO-d6 unless otherwise stated.
Chemical shifts were quoted in parts per million (ppm). 13C
NMR spectral data included the signals for both cis and
trans diastereoisomers. Melting points were determined on
a Fargo MP-2D apparatus (Taiwan, ROC) and are
uncorrected. Solvents, reagents, and tryptophan of L- and
D-forms were obtained from commercial sources and were
used without further purification.
cis/trans ArH, 1H), 7.47–7.51 (m, cis/trans ArH, 2H); 13C
NMR (100 MHz, DMSO-d6) d 16.4, 17.9, 21.9, 22.4, 47.3,
49.5, 51.0, 54.8, 103.7, 104.7, 111.4, 118.2, 119.1, 119.2,
121.9, 125.6, 130.8, 131.0, 136.2, 136.4, 170.3; FAB-
HRMS m/z [MCH]C calcd 231.1134, obsd 231.1140.
4.2.2. Compound 3b. [L-Tryptophan reaction] off-white
solid (68% yield, 50:50 diastereomeric mixture); RfZ0.71
(Butanol/HOAc/H2OZ10:1:1); mp 97–103 8C; 1H NMR
(400 MHz, D2O) d 1.18 (t, JZ2.96 Hz, CH3, 3H), 1.21
(t, JZ4.44 Hz, CH3, 3H), 2.05–2.07 (m, cis MeCH2, 2H),
2.09–2.16 (m, trans MeCH2, 2H), 3.14 (ddd, JZ1.32, 2.40,
14.18 Hz, Trp-NCH2, 1H), 3.40–3.51 (m, cis/trans Trp-
NCH2, 3H), 4.37 (dd, JZ5.12, 12.12 Hz, cis Trp-CHN, 1H),
4.62 (q, JZ6.16 Hz, trans Trp-CHN, 1H), 4.69–4.71
(m, trans EtCHN, 1H), 4.78 (t, JZ6.60 Hz, cis EtCHN,
1H), 7.01–7.08 (qt, JZ0.76, 9.76 Hz, cis/trans ArH, 2H),
7.15 (t, JZ7.12 Hz, cis/trans ArH, 2H), 7.36 (dd, JZ4.96,
8.14 Hz, cis/trans ArH, 2H), 7.48 (d, JZ7.88 Hz, cis/trans
ArH, 2H); 13C NMR (100 MHz, DMSO-d6) d 9.4, 10.0,
21.8, 22.3, 23.9, 25.4, 51.8, 52.6, 54.7, 55.2, 104.2, 105.3,
111.5, 118.1, 119.2, 122.0, 125.6, 129.7, 129.8, 136.3,
136.5, 170.3; FAB-HRMS m/z [MCH]C calcd 245.1290,
obsd 245.1294.
4.2. General procedure for the synthesis of tetrahydro-
b-carbolines at ambient temperature using the Pictet–
Spengler reaction
In a typical reaction, L- or D-tryptophan (255 mg,
1.25 mmol) was dissolved in dichloromethane (12.5 mL)
and trifluoroacetic acid (10%, v/v). The aldehyde or ketone
(5.0 mmol) was added in one portion to the stirred mixture
at room temperature. The reaction was allowed to proceed
until tryptophan was completely consumed as monitored by
TLC using the ninhydrin test (0.5–1 h for aliphatic
aldehydes; 3–4 h for aromatic aldehydes; 12 h–76.5 days
for ketones). Upon completion of the reaction, the reaction
mixture was concentrated to dryness under reduced pressure
to obtain a residue which was dissolved in dichloromethane,
then extracted with acidic water (3!), and lyophilized. In
cases that the product was slightly soluble in dichloro-
methane could result in lower yields. Products were
obtained in excellent purity as determined by NMR and
HPLC.
[D-Tryptophan reaction] off-white solid (69% yield, 49:51
diastereomeric mixture); RfZ0.75 (Butanol/HOAc/H2OZ
10:1:1); mp 95–100 8C; H NMR (400 MHz, D2O) d 1.19
1
(t, JZ2.96 Hz, trans CH3, 3H), 1.21 (t, JZ4.48 Hz, cis
CH3, 3H), 2.05–2.26 (m, cis/trans MeCH2, 4H), 3.14 (ddd,
JZ2.44, 14.06, 14.3 Hz, Trp-NCH2, 1H), 3.25–3.32
(m, Trp-NCH2, 1H), 3.40–3.49 (m, Trp-NCH2, 2H), 4.36
(dd, JZ5.12, 12.6 Hz, cis Trp-CHN, 1H), 4.63 (d, JZ
6.04 Hz, trans Trp-CHN, 1H), 4.65 (m, trans EtCHN, 1H),
4.79 (t, JZ6.64 Hz, cis EtCHN, 1H), 7.05 (qt, JZ1.04,
7.72 Hz, cis/trans ArH, 2H), 7.15 (dd, JZ7.28, 5.74 Hz,
cis/trans ArH, 2H), 7.36 (dd, JZ5.20, 8.14 Hz, cis/trans
ArH, 2H), 7.48 (d, JZ7.84 Hz, cis/trans ArH, 2H); 13C
NMR (100 MHz, D2O–MeOH) d 9.6, 10.2, 23.1, 23.6, 25.8,
27.1, 53.9, 54.7, 56.7, 57.4, 105.7, 106.9, 112.4, 112.5,
119.0, 120.6, 120.7, 123.6, 127.1, 130.0, 130.0, 138.4,
138.6, 171.3; FAB-HRMS m/z [MCH]C calcd 245.1290,
obsd 245.1291.
4.2.1. Compound 3a. [L-Tryptophan reaction] off-white
solid (93% yield, 53:47 diastereomeric mixture); mp 140–
1
148 8C; RfZ0.71 (Butanol/HOAc/H2OZ10:1:1); H NMR
(400 MHz, D2O) d 1.75 (d, JZ2.92 Hz, trans CH3, 3H),
1.77 (d, JZ2.96 Hz, cis CH3, 3H), 3.13 (dd, JZ2.36,
14.18 Hz, trans Trp-NCH2, 1H), 3.23 (dd, JZ1.16, 8.42 Hz,
cis Trp-NCH2, 1H), 3.45 (dt, JZ5.68, 15.28 Hz, cis/trans
Trp-NCH2, 2H), 4.43 (dd, JZ5.42, 12.1 Hz, cis Trp-CHN,
1H), 4.61 (q, JZ5.72 Hz, trans Trp-CHN, 1H), 4.80 (q, JZ
6.72 Hz, trans MeCHN, 1H), 4.93–5.12 (m, cis MeCHN,
1H), 7.04–7.08 (m, cis/trans ArH, 2H), 7.15 (qt, JZ1.24,
8.24 Hz, cis/trans ArH, 2H), 7.35 (dt, JZ0.76, 10.7 Hz, cis/
trans ArH, 2H), 7.48 (dd, JZ2.68, 7.82 Hz, cis/trans ArH,
2H); 13C NMR (100 MHz, DMSO-d6) d 16.5, 17.9, 18.7,
22.0, 22.4, 47.4, 49.5, 51.0, 54.9, 103.7, 104.7, 111.5, 118.2,
119.1, 119.2, 119.8, 121.9, 125.6, 130.9, 131.1, 136.3,
136.4, 170.3; FAB-HRMS m/z [MCH]C calcd 231.1134,
obsd 231.1136.
4.2.3. Compound 3c. [L-Tryptophan reaction] off-white
solid (51% yield, 50:50 diastereomeric mixture); RfZ0.82
(Butanol/HOAc/H2OZ10:1:1); mp 97–106 8C; 1H NMR
(400 MHz, D2O) d 1.06 (t, JZ7.36 Hz, trans CH3, 3H), 1.12
(t, JZ4.56 Hz, cis CH3, 3H), 1.60–1.65 (m, cis/trans CH2,
4H), 1.89–2.01 (m, cis/trans CH2, 2H), 2.08–2.15 (m, CH2,
1H), 2.23–2.34 (m, CH2, 1H), 3.12 (ddd, JZ2.44, 14.16,
28.24 Hz, Trp-NCH2, 1H), 3.26–3.34 (m, Trp-NCH2, 1H),
3.45 (ddd, JZ0.76, 5.46, 16.78 Hz, cis/trans Trp-NCH2,
2H), 4.36 (dd, JZ5.04, 12.08 Hz, cis Trp-CHN, 1H), 4.61
(q, JZ6.16 Hz, trans Trp-CHN, 1H), 4.73–4.75 (m, trans
PrCHN, 1H), 4.82–4.94 (m, cis PrCHN, 1H), 7.06 (dt, JZ
0.84, 7.54 Hz, cis/trans ArH, 2H), 7.15 (t, JZ7.28 Hz, cis/
trans ArH, 2H), 7.35 (t, JZ6.56 Hz, cis/trans ArH, 2H),
7.48 (dd, JZ0.6, 7.84 Hz, cis/trans ArH, 2H); 13C NMR
(100 MHz, DMSO-d6) d 13.8, 13.9, 17.9, 18.4, 21.8, 22.4,
33.0, 34.3, 51.1, 51.9, 53.2, 55.3, 104.1, 105.2, 111.5, 118.6,
119.2, 120.5, 122.0, 125.7, 130.0, 130.1, 136.4, 136.6,
[D-Tryptophan reaction] off-white solid (96% yield, 59:41
diastereomeric mixture); RfZ0.79 (Butanol/HOAc/H2OZ
10:1:1); mp 142–151 8C; 1H NMR (400 MHz, D2O) d 1.74
(d, JZ6.88 Hz, trans CH3, 3H), 1.78 (d, JZ4.64 Hz, cis
CH3, 3H), 3.13 (dd, JZ2.48, 14.14 Hz, trans Trp-NCH2,
1H), 3.24 (dd, JZ1.16, 7.48 Hz, cis Trp-NCH2, 1H), 3.46
(dt, JZ5.34, 15.62 Hz, cis/trans Trp-NCH2, 2H), 4.46 (dd,
JZ5.24, 12.16 Hz, cis Trp-CHN, 1H), 4.62 (q, JZ5.68 Hz,
trans Trp-CHN, 1H), 4.63–4.95 (m, cis/trans MeCHN, 2H),
7.06–7.08 (m, cis/trans ArH, 2H), 7.16 (qt, JZ5.52,
7.04 Hz, cis/trans ArH, 2H), 7.35 (dt, JZ0.76, 8.32 Hz,

12080
F.-M. Kuo et al. / Tetrahedron 60 (2004) 12075–12084
170.3, 170.4; FAB-HRMS m/z [MCH]C calcd 259.1447,
obsd 259.1449.
4.2.5. Compound 3e. [L-Tryptophan reaction] off-white
solid (50% yield, 42:58 diastereomeric mixture); RfZ0.85
(Butanol/HOAc/H2OZ10:1:1); mp 114–122 8C; H NMR
1
(400 MHz, D2O) d 0.93 (t, JZ7.16 Hz, trans CH3, 3H), 0.96
(t, JZ5.72 Hz, cis CH3, 3H), 1.40–1.45 (m, cis/trans
CH2CH2, 8H), 1.61–1.63 (m, cis/trans CH2, 4H), 1.97–
2.05 (m, cis/trans CH2, 2H), 2.13–2.20 (m, CH2, 1H), 2.35–
2.41 (m, CH2, 1H), 3.07 (ddd, JZ2.36, 14.1, 28.36 Hz, Trp-
NCH2, 1H), 3.25–3.35 (m, Trp-NCH2, 1H), 3.38 (dd, JZ
6.00, 16.48 Hz, Trp-NCH2, 1H), 3.45 (dd, JZ1.24, 16.2 Hz,
Trp-NCH2, 1H), 4.12 (dd, JZ5.00, 21.52 Hz, cis Trp-CHN,
1H), 4.37 (t, JZ6.12 Hz, trans Trp-CHN, 1H), 4.66–4.68
(m, trans C5H11CHN, 1H), 4.76–4.79 (m, cis C5H11CHN,
1H), 7.05 (qt, JZ0.84, 7.42 Hz, cis/trans ArH, 2H), 7.14
(dt, JZ1.04, 8.10 Hz, cis/trans ArH, 2H), 7.34 (t, JZ
6.24 Hz, cis/trans ArH, 2H), 7.48 (d, JZ7.88 Hz, cis/trans
ArH, 2H); 13C NMR (100 MHz, DMSO-d6) d 14.1, 22.0,
22.1, 22.6, 24.3, 24.8, 31.1, 31.3, 31.3, 32.4, 51.5, 52.3,
53.7, 55.7, 104.3, 105.4, 111.7, 118.3, 118.8, 119.3, 119.3,
122.0, 122.1, 122.5, 125.9, 130.3, 130.4, 136.6, 136.8,
170.4, 170.5; FAB-HRMS m/z [MCH]C calcd 287.1760,
obsd 287.1757.
[D-Tryptophan reaction] off-white solid (65% yield, 54:46
diastereomeric mixture); RfZ0.82 (Butanol/HOAc/H2OZ
10:1:1); mp 90–98 8C; H NMR (400 MHz, D2O) d 1.06
1
(t, JZ7.68 Hz, trans CH3, 3H), 1.11 (t, JZ5.40 Hz, cis
CH3, 3H), 1.61–1.65 (m, cis/trans CH2, 3H), 1.89–2.01 (m,
cis/ trans CH2, 3H), 2.08–2.15 (m, CH2, 1H), 2.23–2.34 (m,
CH2, 1H), 3.13 (ddd, JZ2.48, 14.12, 28.18 Hz, Trp-NCH2,
1H), 3.23–3.34 (m, Trp-NCH2, 1H), 3.46 (ddd, JZ0.92,
6.00, 19.34 Hz, cis/trans Trp-NCH2, 2H), 4.40 (dd, JZ5.04,
12.10 Hz, cis Trp-CHN, 1H), 4.65 (q, JZ6.08 Hz, trans
Trp-CHN, 1H), 4.74–4.76 (m, trans PrCHN, 1H), 4.80–4.91
(m, cis PrCHN, 1H), 7.06 (t, JZ6.8 Hz, cis/trans ArH, 2H),
7.15 (dt, JZ1.00, 7.62 Hz, cis/trans ArH, 2H), 7.36 (dd, JZ
7.22, 7.10 Hz, cis/trans ArH, 2H), 7.49 (d, JZ7.48 Hz,
cis/trans ArH, 2H); 13C NMR (100 MHz, DMSO-d6) d 14.5,
14.6, 18.7, 19.2, 22.6, 23.1, 33.8, 35.1, 51.9, 52.7, 54.1,
56.0, 104.9, 105.9, 112.3, 119.0, 120.0, 122.8, 122.8, 126.5,
130.8, 130.9, 137.2, 137.4, 171.0, 171.1; FAB-HRMS m/z
[MCH]C calcd 259.1447, obsd 259.1441.
[D-Tryptophan reaction] off-white solid (50% yield, 42:58
diastereomeric mixture); RfZ0.87 (Butanol/HOAc/H2OZ
10:1:1); mp 107–118 8C; 1H NMR (200 MHz, D2O) d 0.94
(t, JZ7.12 Hz, trans CH3, 3H), 0.96 (t, JZ6.92 Hz, cis
CH3, 3H), 1.28–1.60 (m, cis/trans CH2CH2, 8H), 1.61–1.62
(m, cis/trans CH2, 4H), 1.97–2.05 (m, cis/trans CH2, 2H),
2.13–2.20 (m, CH2, 1H), 2.35–2.41 (m, CH2, 1H), 3.07
(ddd, JZ2.48, 14.2, 28.26 Hz, Trp-NCH2, 1H), 3.23–3.28
(m, Trp-NCH2, 1H), 3.33–3.48 (m, cis/trans Trp-NCH2,
2H), 4.12 (dd, JZ5.00, 12.10 Hz, cis Trp-CHN, 1H), 4.37
(t, JZ6.16 Hz, trans Trp-CHN, 1H), 4.66–4.68 (m, trans
C5H11CHN, 1H), 4.79–4.81 (m, cis C5H11CHN, 1H), 7.04–
7.07 (m, cis/trans ArH, 2H), 7.14 (dt, JZ1.04, 7.62 Hz,
cis/trans ArH, 2H), 7.34 (t, JZ7.24 Hz, cis/trans ArH, 2H),
7.48 (d, JZ7.72 Hz, cis/trans ArH, 2H); 13C NMR
(50 MHz, DMSO-d6) d 13.9, 21.9, 22.6, 24.1, 24.6, 31.2,
31.2, 51.0, 52.4, 55.9, 104.5, 105.6, 111.4, 118.0, 118.9,
121.7, 125.7, 130.4, 130.5, 136.3, 136.4, 170.28, 170.4;
FAB-HRMS m/z [MCH]C calcd 287.1760, obsd 287.1761.
4.2.4. Compound 3d. [L-Tryptophan reaction] off-white
solid (58% yield, 50:50 diastereomeric mixture); RfZ0.83
(Butanol/HOAc/H2OZ10:1:1); mp 114–122 8C; H NMR
1
(200 MHz, D2O) d 0.99 (t, JZ7.32 Hz, trans CH3, 3H), 1.02
(t, JZ7.28 Hz, CH3, 3H), 1.45–1.61 (m, cis/trans CH2CH2,
8H), 1.97–2.05 (m, cis/trans CH2, 2H), 2.13–2.20 (m, CH2,
1H), 2.35–2.41 (m, CH2, 1H), 3.11 (ddd, JZ2.36, 14.14,
28.26 Hz, Trp-NCH2, 1H), 3.25–3.32 (m, Trp-NCH2, 1H),
3.43 (dd, JZ6.00, 21.1 Hz, cis/trans Trp-NCH2, 2H), 4.25
(dd, JZ7.04, 12.12 Hz, cis Trp-CHN, 1H), 4.52 (q, JZ
1.08 Hz, trans Trp-CHN, 1H), 4.63–4.82 (m, BuCHN, 2H),
7.05 (qt, JZ0.8, 7.50 Hz, cis/trans ArH, 2H), 7.15 (t, JZ
7.76 Hz, cis/trans ArH, 2H), 7.48 (d, JZ7.84 Hz, cis/trans
ArH, 2H), 7.47–7.49 (m, cis/trans ArH, 2H); 13C NMR
(50 MHz, DMSO-d6) d 13.8, 22.1, 22.1, 22.5, 26.6, 27.1,
30.8, 32.0, 51.1, 52.3, 53.3, 55.8, 104.5, 105.6, 111.5, 118.1,
119.5, 121.8, 125.8, 130.3, 130.4, 136.4, 136.4, 136.6,
170.4, 170.5; FAB-HRMS m/z [MCH]C calcd 273.1603,
obsd 273.1605.
4.2.6. Compound 3f. [L-Tryptophan reaction] off-white
solid (56% yield, 27:73 diastereomeric mixture); RfZ0.83
(Butanol/HOAc/H2OZ10:1:1); mp 132– 141 8C; H NMR
[D-Tryptophan reaction] off-white solid (76% yield, 54:46
diastereomeric mixture); RfZ0.85 (Butanol/HOAc/H2OZ
10:1:1); mp 110–118 8C; 1H NMR (200 MHz, D2O) d 0.99
(t, JZ4.88 Hz, trans CH3, 3H), 1.03 (t, JZ3.24 Hz, cis
CH3, 3H), 1.45–1.59 (m, cis/trans CH2CH2, 8H), 1.97–2.05
(m, cis/trans CH2, 2H), 2.13–2.20 (m, CH2, 1H), 2.35–2.41
(m, CH2, 1H), 3.13 (dt, JZ2.24, 13.48 Hz, Trp-NCH2, 1H),
3.26–3.32 (m, Trp-NCH2, 1H), 3.45 (dt, JZ6.00, 19.76 Hz,
cis/trans Trp-NCH2, 2H), 4.35 (dd, JZ5.04, 12.06 Hz, cis
Trp-CHN, 1H), 4.60 (t, JZ6.24 Hz, trans Trp-CHN, 1H),
4.72–4.84 (m, cis/trans BuCHN, 2H), 7.06 (t, JZ7.16 Hz,
cis/trans ArH, 2H), 7.15 (t, JZ7.72 Hz, cis/trans ArH, 2H),
77.36 (dd, JZ5.08, 8.04 Hz, cis/trans ArH, 2H), 7.48 (d,
JZ7.72 Hz, cis/trans ArH, 2H); 13C NMR (100 MHz,
DMSO-d6) d 13.8, 13.8, 22.1, 22.2, 22.7, 26.6, 27.1, 30.9,
32.0, 51.0, 52.6, 53.3, 56.2, 104.7, 105.8, 111.5, 118.1,
119.0, 119.1, 121.8, 125.8, 130.5, 130.6, 136.4, 136.6,
170.4, 170.6; FAB-HRMS m/z [MCH]C calcd 273.1603,
obsd 273.1600.
1
(400 MHz, D2O) d 3.11–3.22 (m, cis/trans Trp-NCH2, 2H),
3.28–3.34 (m, phCH2, 2H), 3.44–3.48 (m, cis/trans Trp-
NCH2, 1H), 3.55 (dd, JZ5.68, 14.38 Hz, phCH2, 2H), 3.63–
3.71 (m, Trp-NCH2, 1H), 4.04–4.07 (m, cis/trans Trp-CHN,
2H), 4.91–4.93 (m, cis BzCHN, 1H), 5.17 (t, JZ6.28 Hz,
trans BzCHN, 1H), 7.04–7.52 (m, cis/trans ArH, 18H); 13C
NMR (50 MHz, DMSO-d6) d 21.8, 22.5, 37.0, 38.0, 52.4,
54.7, 55.7, 104.9, 105.4, 111.6, 118.3, 119.2, 119.3, 122.1,
125.7, 127.4, 128.8, 129.3, 129.6, 129.7, 129.8, 135.3,
135.6, 136.4, 136.5, 170.1, 170.6; FAB-HRMS m/z
[MCH]C calcd 307.1447, obsd 307.1446.
[D-Tryptophan reaction] off-white solid (63% yield, 26:74
diastereomeric mixture); RfZ0.81 (Butanol/HOAc/H2OZ
10:1:1); mp 131–140 8C; 1H NMR (400 MHz, D2O) d 3.12–
3.29 (m, cis/trans Trp-NCH2, 2H), 3.30 (m, trans PhCH2,
2H), 3.46–3.49 (m, Trp-NCH2, 1H), 3.57 (dd, JZ5.80,

F.-M. Kuo et al. / Tetrahedron 60 (2004) 12075–12084
12081
14.40 Hz, cis PHCH2, 2H), 3.80 (dd, JZ3.92, 14.58 Hz,
Trp-NCH2, 1H), 4.17–4.21 (m, cis/trans Trp-CHN, 2H),
4.94–4.97 (t, cis BzCHN, 1H), 5.19 (t, JZ6.16 Hz, trans
BzCHN, 1H), 7.07–7.48 (m, cis/trans ArH 18H); 13C NMR
(50 MHz, DMSO-d6) d 21.9, 22.5, 37.1, 38.0, 52.3, 54.6,
55.7, 105.0, 105.5, 111.6, 118.2, 119.2, 119.3, 122.1, 125.7,
127.3, 128.8, 128.8, 129.5, 129.6, 129.8, 135.3, 135.8,
136.4, 136.5, 170.3, 170.7; FAB-HRMS m/z [MCH]C
calcd 307.1447, obsd 307.1452.
118.2, 118.3, 119.2, 120.2, 122.0, 122.2, 125.5, 125.6,
128.4, 129.2, 129.6, 129.8, 130.2, 130.3, 131.1, 131.8,
135.9, 136.7, 136.8, 139.4, 139.6, 170.0, 170.2; FAB-
HRMS m/z [MCH]C calcd 307.1447, obsd 307.1440.
4.2.9. Compound 3i. [D-Tryptophan reaction] off-white
solid (95% yield, 58:42 diasteromeric mixture); RfZ0.79
1
(Butanol/HOAc/H2OZ10:1:1); mp 121–131 8C; H NMR
(200 MHz, D2O) d 1.09 (t, JZ7.60 Hz, CH3, 3H), 1.12
(t, JZ7.48 Hz, CH3, 3H), 1.74 (s, CH3, 3H), 1.83 (s, CH3,
3H), 1.98–2.08 (m, CH2, 1H), 2.11–2.23 (m, CH2, 2H),
2.32–2.39 (m, CH2, 1H), 3.12 (ddd, JZ2.64, 7.86,
23.48 Hz, Trp-NCH2, 2H), 3.45–3.52 (m, Trp-NCH2, 2H),
4.51 (dd, JZ5.12, 11.90 Hz, Trp-CHN, 1H), 4.65 (dd, JZ
5.72, 11.80 Hz, Trp-CHN, 1H), 7.05 (t, JZ7.16 Hz, ArH,
2H), 7.15 (dt, JZ1.16, 8.82 Hz, ArH, 2H), 7.35 (t, JZ
7.12 Hz, ArH, 2H), 7.48 (dd, JZ4.24, 7.84 Hz, ArH, 2H);
13C NMR (50 MHz, DMSO-d6) d 7.5, 8.9, 22.0, 22.3, 22.9,
30.0, 31.2, 51.0, 51.9, 59.7, 59.7, 103.7, 103.9, 111.4, 118.2,
119.1, 121.9, 125.4, 125.4, 133.2, 134.4, 136.2, 136.3,
170.3, 170.5; FAB-HRMS m/z [MCH]C calcd 259.1447,
obsd 259.1445.
4.2.7. Compound 3g. [L-Tryptophan reaction] off-white
solid (95% yield, 61:39 diastereomeric mixture); RfZ0.79
1
(Butanol/HOAc/H2OZ10:1:1); mp 175–182 8C; H NMR
(400 MHz, D2O) d 3.34–3.41 (m, cis/trans Trp-NCH2, 2H),
3.55–3.61 (m, cis/trans Trp-NCH2, 2H), 4.42 (q, JZ
6.96 Hz, trans Trp-CHN, 1H), 4.60 (dd, JZ5.16,
12.02 Hz, cis Trp-CHN, 1H), 5.90 (s, cis PhCHN, 1H),
6.05 (s, trans PhCHN, 1H), 7.10–7.56 (m, cis/trans ArH,
18H); 13C NMR (50 MHz, DMSO-d6) d 22.0, 22.3, 52.3,
55.5, 57.0, 58.4, 106.9, 107.4, 111.8, 118.7, 120.2, 123.2,
125.5, 127.4, 128.5, 129.5, 129.7, 129.9, 130.7, 130.9,
132.7, 133.3, 136.9, 171.8, 172.1; FAB-HRMS m/z
[MCH]C calcd 293.1290, obsd 293.1284.
4.2.10. Compound 3j. [D-Tryptophan reaction] off-white
solid (96% yield); RfZ0.69 (Butanol/HOAc/H2OZ10:1:1);
mp 89–97 8C; H NMR (200 MHz, D2O) d 1.03 (t, JZ
[D-Tryptophan reaction] off-white solid (98% yield, 64:36
diastereomeric mixture); RfZ0.78 (Butanol/HOAc/H2OZ
10:1:1); mp 163–174 8C; 1H NMR (200 MHz, D2O) d 3.31–
3.42 (m, cis/trans Trp-NCH2, 2H), 3.59 (dd, JZ4.94,
16.2 Hz, cis/trans Trp-NCH2, 2H), 4.45 (q, JZ5.80 Hz,
trans Trp-CHN, 1H), 4.61 (dd, JZ5.12, 12.10 Hz, cis Trp-
CHN, 1H), 5.59 (s, cis PhCHN, 1H), 6.06 (s, trans PhCHN,
1H), 7.14–7.58 (m, cis/trans ArH, 18H); 13C NMR
(50 MHz, DMSO-d6) d 22.5, 51.8, 54.9, 55.9, 57.9, 106.4,
107.2, 111.9, 114.2, 118.5, 119.5, 120.1, 122.3, 125.8,
128.2, 128.9, 129.2, 130.2, 130.6, 129.9, 134.1, 134.6,
137.0, 137.1, 170.0, 170.2; FAB-HRMS m/z [MCH]C
calcd 293.1290, obsd 293.1284.
1
7.56 Hz, CH3, 3H), 1.08 (t, JZ7.56 Hz, CH3, 3H), 2.02–
2.20 (m, CH2, 3H), 2.39 (h, JZ7.44 Hz, CH2, 1H), 3.14 (dd,
JZ12.0, 16.24 Hz, Trp-NCH2, 1H), 3.47 (dd, JZ5.6,
16.4 Hz, Trp-NCH2, 1H), 4.56 (dd, JZ12.0, 5.6 Hz, Trp-
CHN, 1H), 7.05 (t, JZ7.36 Hz, ArH, 1H), 7.14 (t, JZ
7.24 Hz, ArH, 1H), 7.37 (d, JZ8.15 Hz, ArH, 1H), 7.47
(d, JZ7.84 Hz, ArH, 1H); 13C NMR (50 MHz, DMSO-d6) d
7.2, 8.9, 22.3, 27.5, 28.2, 51.6, 62.9, 104.5, 111.5, 118.3,
119.1, 122.0, 125.5, 132.7, 136.4, 170.5; FAB-HRMS m/z
[MCH]C calcd 273.1603, obsd 273.1604.
4.2.11. Compound 3k. [D-Tryptophan reaction] off-white
solid (82% yield); RfZ0.81 (Butanol/HOAc/H2OZ10:1:1);
mp 158–166 8C; H NMR (400 MHz, CD3OD-d4) d 1.51–
4.2.8. Compound 3h. [L-Tryptophan reaction] off-white
solid (76% yield, 62:38 tereomeric mixture); RfZ0.87
(Butanol/HOAc/H2OZ10:1:1); mp 140–151 8C; H NMR
1
1
2.14 (m, Ch, 8H), 2.29–2.36 (m, Ch, 2H), 3.10 (dd, JZ
11.76, 16.26 Hz, Trp-NCH2, 1H), 3.46 (dd, JZ5.36,
16.28 Hz, Trp-NCH2, 1H), 4.40 (dd, JZ5.36, 11.62 Hz,
Trp-CHN, 1H), 7.05 (dt, JZ1.08, 7.41 Hz, ArH, 1H), 7.15
(dt, JZ1.08, 7.66 Hz, ArH, 1H), 7.38 (d, JZ8.08 Hz, 1H),
7.48 (d, JZ7.88 Hz, ArH, 1H); 13C NMR (50 MHz, DMSO-
d6) d 20.7, 23.8, 24.5, 33.7, 34.6, 52.3, 57.0, 104.9, 111.6,
118.1, 119.0, 121.6, 125.5, 125.8, 136.0, 136.3, 136.7,
171.8; FAB-HRMS m/z [MCH]C calcd 285.1603, obsd
285.1608.
(400 MHz, D2O) d 2.37 (s, trans CH3, 3H), 2.41 (s, cis CH3,
3H), 3.29–3.34 (m, cis/trans Trp-NCH2, 2H), 3.54–3.59 (m,
cis/trans Trp-NCH2, 2H), 4.40 (q, JZ5.76 Hz, trans Trp-
NCH, 1H), 4.55 (dd, JZ5.16, 13.18 Hz, cis Trp-NCH, 1H),
5.84 (s, cis ArCHN, 1H), 6.00 (s, trans ArCHN, 1H), 7.10–
7.56 (m, cis/trans ArH, 16H); 13C NMR (50 MHz,
DMSO-d6) d 20.8, 20.9, 22.3, 51.3, 54.4, 55.5, 57.5,
106.1, 106.8, 111.7, 118.3, 118.4, 119.2, 120.2, 122.0,
122.3, 125.5, 125.6, 128.2, 129.2, 130.4, 130.9, 131.5,
136.7, 136.9, 139.5, 139.6, 170.0, 170.1; FAB-HRMS m/z
[MCH]C calcd 307.1447, obsd 307.1444.
4.2.12. Compound 3l. [D-Tryptophan reaction] off-white
solid (72% yield); RfZ0.75 (Butanol/HOAc/H2OZ10:1:1);
mp 128–136 8C; 1H NMR (200 MHz, D2O) d 1.98–2.16 (m,
Cp, 4H), 2.31 (p, JZ5.68 Hz, Cp, 2H), 2.49 (p, JZ8.00 Hz,
Cp, 1H), 3.12 (dd, JZ12.0, 16.12 Hz, Trp-NCH2, 1H), 3.47
(dd, JZ5.36, 16.12 Hz, Trp-NCH2, 1H), 4.45 (dd, JZ5.16,
12.06 Hz, Trp-CHN, 1H), 7.05 (dt, JZ0.96, 7.52 Hz, ArH,
1H), 7.15 (dt, JZ1.16, 7.66 Hz, ArH, 1H), 7.36 (d, JZ
4.12 Hz, ArH, 1H), 7.48 (d, JZ7.88 Hz, ArH, 1H); 13C
NMR (50 MHz, DMSO-d6) d 22.7, 24.9, 25.0, 37.4, 53.2,
59.4, 61.6, 65.9, 103.8, 106.5, 111.5, 114.2, 118.1, 118.8,
119.2, 120.5, 122.0, 121.9, 125.4, 127.4, 134.5, 134.7,
[D-Tryptophan reaction] off-white solid (81% yield, 58:42
diasteromeric mixture); RfZ0.87 (Butanol/HOAc/H2OZ
10:1:1); mp 136–146 8C; 1H NMR (400 MHz, D2O) d 2.37
(s, trans CH3, 3H), 2.41 (s, cis CH3, 3H), 3.31–3.40 (m,
cis/trans Trp-NCH2, 2H), 3.54–3.60 (m, cis/trans Trp-
NCH2, 2H), 4.39 (q, JZ5.76 Hz, trans Trp-CHN, 1H), 4.57
(dd, JZ5.20, 12.02 Hz, Trp-CHN, 1H), 5.84 (s, cis ArCHN,
1H), 6.00 (s, trans ArCHN, 1H), 7.08–7.87 (m, cis/trans
ArH, 16H); 13C NMR (50 MHz, DMSO–d6) d 20.8, 20.9,
22.2, 22.4, 51.4, 54.4, 55.6, 57.5, 106.1, 106.8, 111.6, 111.7,

12082
F.-M. Kuo et al. / Tetrahedron 60 (2004) 12075–12084
136.6, 136.9, 170.5, 170.7; FAB-HRMS m/z [MCH]C
calcd 271.1447, obsd 271.1456.
DMSO-d6) d 20.6, 23.6, 24.3, 30.8, 33.6, 34.4, 52.0, 56.8,
57.2, 104.6, 105.4, 110.9, 111.5, 117.3, 118.1, 118.7, 119.0,
120.8, 121.6, 125.7, 127.5, 135.2, 136.2, 136.4, 170.9,
171.7; FAB-HRMS m/z [MCH]C calcd 285.1603, obsd
285.1608.
4.3. General procedure for the microwave-accelerated
Pictet–Spengler reaction of L-tryptophan with ketones
In a typical reaction, L-tryptophan (51 mg, 0.25 mmol) was
dissolved in toluene (2.5 mL) and trifluoroacetic acid (10%,
v/v). The ketone (3.0 mmol) was added in one portion to the
mixture. The microwave-assisted Pictet–Spengler reaction
was carried out in an open vessel and temperature-
controlled at 60 8C using a commercial microwave oven
(300 W, Synthewave 402, Prolabo). A 50% microwave
power was applied throughout the reaction period to avoid
formation of side products of unknown structure. The
reaction was allowed to proceed until tryptophan was
completely consumed as monitored by TLC using the
ninhydrin test or HPLC at 280 nm (10 min–40 h). Upon
completion of the reaction, the reaction mixture was
concentrated to dryness under reduced pressure to obtain a
residue which was dissolved in toluene, then extracted with
acidic water (3!), and lyophilized. Products were obtained
in excellent purity as determined by NMR and HPLC.
4.3.4. Compound 3l. [L-Tryptophan reaction] off-white
solid (81% yield); RfZ0.81 (Butanol/HOAc/H2OZ10:1:1);
mp 132–143 8C; 1H NMR (400 MHz, D2O) d 1.99–2.17 (m,
Cp, 4H), 2.77 (p, JZ6.56 Hz, Cp, 1H), 2.50 (p, JZ8.04 Hz,
Cp, 1H), 3.12 (dd, JZ12.6, 16.16 Hz, Trp-NCH2, 1H), 3.48
(dd, JZ5.28, 15.56 Hz, Trp-NCH2, 1H), 4.47 (q, JZ5.32,
11.98 Hz, Trp-CHN, 1H), 7.06 (dt, JZ1.72, 8.48 Hz, ArH,
1H), 7.15 (dt, JZ1.12, 13.64 Hz, ArH, 1H), 7.37 (d, JZ
7.36 Hz, ArH, 1H), 7.47 (d, JZ7.88 Hz, ArH, 1H); 13C
NMR (50 MHz, DMSO-d6) d 22.6, 24.8, 25.0, 37.4, 38.3,
53.1, 66.0, 103.7, 111.5, 118.2, 119.2, 122.0, 125.4, 134.7,
136.6, 170.5; FAB-HRMS m/z [MCH]C calcd 271.1447,
obsd 271.1437.
4.3.5. Compound 3m. [L-Tryptophan reaction] off-white
solid (62% yield, 22:78 diasteromeric mixture); RfZ0.80
1
(Butanol/HOAc/H2OZ10:1:1); mp 154–159 8C; H NMR
(200 MHz, D2O) d 2.14 (s, CH3, 3H), 2.25 (s, CH3, 3H),
3.05–3.10 (m, Trp-NCH2, 2H), 3.30–3.41 (m, Trp-NCH2,
2H), 3.73–3.78 (m, Trp-CHN, 1H), 4.47–4.51 (m, Trp-
CHN, 1H), 7.13–7.58 (m, ArH, 18H); 13C NMR (100 MHz,
DMSO-d6) d 22.5, 23.0, 23.7, 24.8, 52.3, 52.9, 61.6, 61.9,
106.2, 106.3, 111.8, 111.9, 118.7, 118.9, 119.5, 122.7,
125.7, 125.7, 128.2, 128.7, 128.8, 129.0, 129.5, 129.7,
132.5, 133.8, 136.9, 138.8, 170.2, 170.3; FAB-HRMS m/z
[MCH]C calcd 307.1447, obsd 307.1441.
4.3.1. Compound 3i. [L-Tryptophan reaction] off-white
solid (87% yield, 58:42 diasteromeric mixture); RfZ0.75
(Butanol/HOAc/H2OZ10:1:1); mp 122–130 8C; H NMR
1
(200 MHz, D2O) d 1.06–1.14 (m, CH3, 6H), 1.74 (s, CH3,
3H), 1.83 (s, CH3, 3H), 2.00–2.06 (m, CH2, 1H), 2.12–2.21
(m, CH2, 2H), 2.26–2.33 (m, CH2, 1H), 3.10 (dd, JZ12.84,
15.94 Hz, Trp-NCH2, 2H), 3.43–3.51 (m, Trp-NCH2, 2H),
4.40 (dd, JZ3.84, 11.82 Hz, Trp-CHN, 1H), 4.53 (q, JZ
3.84 Hz, trans Trp-CHN, 1H), 7.03–7.07 (m, ArH, 2H),
7.12–7.17 (m, ArH, 2H), 7.32–7.36 (m, ArH, 2H), 7.45–
7.49 (m, ArH, 2H); 13C NMR (50 MHz, D2O–MeOH) d 6.8,
8.2, 22.0, 22.1, 22.6, 31.7, 51.9, 52.7, 60.4, 60.6, 104.0,
104.2, 111.7, 113.6, 118.5, 119.4, 120.1, 123.0, 125.3,
132.7, 133.7, 136.5, 136.6, 171.5, 171.7; FAB-HRMS m/z
[MCH]C calcd 259.1447, obsd 259.1445.
4.3.6. Compound 3n. [L-Tryptophan reaction] off-white
solid (99% yield, 67:32 diasteromeric mixture); RfZ0.73
(Butanol/HOAc/H2OZ10:1:1); mp 88–93 8C; 1H NMR
(200 MHz, D2O) d 0.94 (d, JZ7.04 Hz, CH3, 3H), 1.05
(dd, JZ8.48, 8.00 Hz, CH3, 6H), 1.23 (d, JZ7.00 Hz, CH3,
3H), 1.70 (s, CH3, 3H), 1.75 (s, CH3, 3H), 2.18 (p, JZ
6.84 Hz, (CH3)2CH, 1H), 2.55 (p, JZ7.04 Hz, (CH3)2CH,
1H), 3.11–3.22 (m, Trp-NCH2, 2H), 3.38–3.45 (m, Trp-
NCH2, 2H), 4.35 (dd, JZ4.80, 11.9 Hz, cis Trp-CHN, 1H),
4.51 (t, JZ5.62 Hz, trans Trp-CHN, 1H), 7.03 (t, JZ
7.04 Hz, ArH, 1H), 7.13 (t, JZ6.16 Hz, ArH, 1H), 7.37 (d,
JZ8.20 Hz, ArH, 1H), 7.43 (d, JZ7.64 Hz, ArH, 1H); 13C
NMR (50 MHz, DMSO-d6) d 16.6, 17.2, 17.5, 18.4, 22.2,
22.7, 34.6, 35.7, 51.0, 52.8, 62.5, 63.5, 103.7, 105.1, 111.5,
118.2, 119.1, 121.9, 125.5, 134.2, 136.2, 136.6, 169.9,
170.3; FAB-HRMS m/z [MCH]C calcd 273.1603, obsd
273.1601.
4.3.2. Compound 3j. [L-Tryptophan reaction] off-white
solid (88% yield); RfZ0.67 (Butanol/HOAc/H2OZ10:1:1);
1
mp 83–92 8C; H NMR (200 MHz, D2O) d 1.04 (t, JZ
7.56 Hz, CH3, 3H), 1.08 (t, JZ7.52 Hz, CH3, 3H), 2.07–
2.20 (m, CH2, 3H), 2.36–2.44 (m, CH2, 1H), 3.14 (dd, JZ
11.84, 16.24 Hz, Trp-NCH2, 1H), 3.49 (dd, JZ5.56,
16.28 Hz, Trp-NCH2, 1H), 4.61 (dd, JZ5.40, 11.84 Hz,
Trp-CHN, 1H), 7.05 (t, JZ7.08 Hz, ArH, 1H), 7.15 (dt, JZ
1.12, 8.00 Hz, ArH, 1H), 7.36 (d, JZ8.12 Hz, ArH, 1H),
7.49 (d, JZ7.88 Hz, ArH, 1H); 13C NMR (50 MHz,
DMSO-d6) d 7.1, 8.8, 22.2, 27.4, 28.2, 51.5, 62.9, 104.4,
111.4, 118.2, 119.0, 121.9, 125.4, 132.6, 136.3, 170.4;
FAB-HRMS m/z [MCH]C calcd 273.1603, obsd 273.1595.
4.4. Procedures for the preparation of demethoxy-
fumitremorgin C analog 4 and tetrahydro-b-
carbolinehydantoins 5a–c
4.3.3. Compound 3k. [L-Tryptophan reaction] off-white
solid (84% yield); RfZ0.77 (Butanol/HOAc/H2OZ10:1:1);
mp 160–168 8C; H NMR (400 MHz, CD3OD-d4) d 1.51–
2.14 (m, Ch, 8H), 2.29–2.36 (m, Ch, 2H), 3.10 (dd, JZ
11.76, 16.26 Hz, Trp-NCH2, 1H), 3.46 (dd, JZ5.36,
16.28 Hz, Trp-NCH2, 1H), 4.40 (dd, JZ5.36, 11.62 Hz,
Trp-CHN, 1H), 7.05 (dt, JZ1.08, 7.41 Hz, ArH, 1H), 7.15
(dt, JZ1.08, 7.66 Hz, ArH, 1H), 7.38 (d, JZ8.08 Hz, 1H),
7.48 (d, JZ7.88 Hz, ArH, 1H); 13C NMR (50 MHz,
The experimental procedures for preparing compounds 4
and 5 were not optimized. Using the protocol described in
Section 4.3, L-tryptophan methyl ester (50 mg, 0.23 mmol)
was, first, reacted with acetone (0.3 mL) in the presence of
microwaves (60 8C, 60 W) to form the corresponding 1,1-
dimethyl 1,2,3,4-tetrahydro-b-carboline. In the case of
compound 4 synthesis, after the acylation reaction with
the acid chloride (5 equiv) formed from Fmoc-protected
1

F.-M. Kuo et al. / Tetrahedron 60 (2004) 12075–12084
12083
L-proline (5 equiv) with excessive thionyl chloride, the
Fmoc-deprotection and subsequent cyclization to form the
diketopiperazine ring was achieved by piperidine (20% in
methylene chloride). Without attempting to optimize its
overall yield, compound 4 was isolated as white solid in
O95% purity as a single stereoisomer after the aqueous
wash and silica gel column chromatography. In cases of
preparingcompounds5a–5c, 1,1-dimethyl 1,2,3,4-tetrahydro-
b-carboline from the Pictet–Spengler reaction was mixed
with butyl isocyanate, phenyl isothiocyanate, or allyl
isocyanate (1.1 equiv) in methyl ethyl ketone, and the
reaction was carried out at 60 8C under low-power
microwave condition (60 W). The progress of the reaction
was monitored using TLC (typically 2 min for all three
reactions). Upon the completion of the reactions, the
solution mixtures containing the desired tetrahydro-b-
carbolinehydantoins 5a–5c were evaporated in vacuo and
purified by silica gel column chromatography (ethyl acetate/
hexaneZ1:4). The products were afforded as off-white
solid.
4.4.4. Compound 5c. Off-white solid (80 mg, 66% yield);
mp 232–236 8C; 1H NMR (400 MHz, CDCl3) d 1.74
(s, CH3, 3H), 2.03 (s, CH3, 3H), 2.82 (dd, JZ2.5,
11.4 Hz, Trp-CH2, 1H), 3.39 (dd, JZ4.5, 10.4 Hz, Trp-
CH2, 1H), 4.18 (d, JZ5.7 Hz, NCH2, 2H), 4.27 (dd, JZ4.5,
6.9 Hz, Trp-CHN, 1H), 5.21 (dt, JZ1.1, 3.4 Hz, CH]CH2,
2H), 5.8–5.9 (m, CH]CH2(1H), 2H), 7.21–7.23 (m, Trp-
ArH, 2H), 7.33 (d, JZ11.0 Hz, Trp-ArH, 1H), 7.50 (d, JZ
7.6 Hz, Trp-ArH, 1H), 8.46 (s, indole, 1H); 13C NMR
(100 MHz, CDCl3) d 22.8, 25.9, 28.1, 40.6, 55.5, 56.1,
105.1, 111.1, 116.1, 118.1, 118.3, 119.8, 122.4, 126.1,
131.2, 136.1, 138.6, 154.1, 171.5; FAB-HRMS for
C18H20O2N3 [(MCH)C] calcd 310.1556, found 310.1562.
Acknowledgements
We gratefully acknowledge support of this research through
grants from the National Science Council (Taiwan, ROC)
(NSC92-2751-B-001-014-Y, NSC92-2218-E-194-015,
NSC91-2218-E-194-012, and NSC91-2113-M-194-023).
We thank Professor Shui-Tein Chen (Institute of Biological
Chemistry, Academia Sinica, Taipei, Taiwan) for a loan of
the focused microwave apparatus used in this study. We
thank Yi-Chun Wang for the acquisition of some NMR
spectra. A predoctoral fellowship from the NSC to M.-C.T.
is gratefully acknowledged.
4.4.1. Compound 4. White solid (8.1 mg, 11%); mp 194 8C
(dec); H NMR (400 MHz, CDCl3) d 1.88–2.13 (m, Pro-
1
CH2CH2, 3H), 1.90 (s, CH3, 3H), 1.95 (s, CH3, 3H), 2.42–
2.48 (m, Pro-CH2CH2, 1H), 2.93 (dd, JZ11.6, 16.1 Hz,
Trp-CH2, 1H), 3.49–3.63 (m, Pro-NCH2, 1H), 3.70–3.78
(m, Pro-NCH2 (1H), Trp-NCH2 (1H), 2H), 4.09–4.13 (m,
Pro-CHN, 1H), 4.26 (dd, JZ2.9, 10.6 Hz, Trp-CHN, 1H),
7.13–7.22 (m, ArH, 4H), 7.36 (d, JZ7.9 Hz, ArH, 1H), 7.58
(d, JZ7.7 Hz, ArH, 1H), 8.01 (br s, indole NH, 1H); 13C
NMR (100 MHz, CDCl3) d 22.1, 23.8, 24.9, 29.8, 30.3,
45.5, 57.2, 59.7, 59.8, 105.7, 110.9, 118.6, 120.0, 122.3,
126.2, 136.1, 138.3, 164.4, 168.8.; FAB-HRMS calcd for
C19H22N3O2 ([MCH]C) 324.1712, found 324.1719.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2004.10.
025
4.4.2. Compound 5a. Off-white solid (89 mg, 70% yield);
mp 192–193 8C; 1H NMR (400 MHz, CDCl3) d 0.94 (t, JZ
7.4 Hz, CH3, 3H), 1.25–1.40 (m, CH2, 2H), 1.58–1.68 (m,
CH2, 2H), 1.74 (s, CH3, 3H), 2.03 (s, CH3, 3H), 2.80 (dd,
JZ3.4, 11 Hz, Trp-CH2, 1H), 3.38 (dd, JZ4.5, 10.3 Hz,
Trp-CH2, 1H), 3.55 (t, JZ7.4 Hz, NCH2, 2H), 4.22 (dd, JZ
4.5, 6.8 Hz, Trp-CHN, 1H), 7.15 (dt, JZ0.7, 7 Hz, Trp-
ArH, 1H), 7.21 (dt, JZ1.1, 7.0 Hz, Trp-ArH, 1H), 7.35 (d,
JZ8.0 Hz, Trp-ArH, 1H), 7.50 (d, JZ7.72 Hz, Trp-ArH,
1H), 8.34 (s, indolyl NH, 1H); 13C NMR (100 MHz, CDCl3)
d 13.6, 20.1, 22.8, 26.0, 28.1, 30.2, 55.3, 56.0, 105.3, 111.0,
118.3, 120.0, 122.4, 126.1, 136.1, 138.6, 154.6, 171.9;
FAB-HRMS for C19H24N3O2: ([MCH]C) calcd 326.1869,
found 326.1873.
References and notes
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1
3H), 2.33 (s, CH3, 3H), 2.99 (dd, JZ3.6, 11.4 Hz, Trp-CH2,
1H), 3.53 (dd, JZ4.4, 10.6 Hz, Trp-CH2, 1H), 4.52 (dd, JZ
4.4, 7.0 Hz, Trp-CHN, 1H), 7.15–7.21 (m, Trp-ArH, 2H),
7.34–7.40 (m, Trp-ArH(2H), Ph(1H), 3H), 7.43–7.56 (m,
Ph, 4H), 7.91 (s, indole NH, 1H); 13C NMR (100 MHz,
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111.4, 118.4, 119.1, 121.7, 125.8, 126.0, 128.8, 128.9,
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171.4, 173.0, 179.6, 179.8; FAB-HRMS for C21H20ON3S:
(MCH)C calcd 362.1327, found 362.1335.

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