A convenient synthesis of conformationally constrained β-substituted tryptophans

Article abstract of DOI:10.1016/S0040-4020(00)00446-4

A short and general synthesis for the preparation of various conformationally constrained β-substituted tryptophans has been elaborated starting from indole, aldehydes and Meldrum's acid by using trimolecular condensation and Curtius rearrangement mediate

Full text of DOI:10.1016/S0040-4020(00)00446-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5479±5492
A Convenient Synthesis of Conformationally Constrained
b-Substituted Tryptophans
²
Csaba Nemes, Laurent Jeannin, Janos Sapi, Marie Laronze, Houria Seghir, Franck Auge
³
Â
*
and Jean-Yves Laronze
Á Â Â
UPRES A CNRS 6013 `Isolement, Structure, Transformations et Synthese de Produits Naturels', IFR 53 Biomolecules, Faculte de Pharmacie,
Â
Universite de Reims-Champagne-Ardenne, 51, rue Cognacq-Jay, F-51096 Reims Cedex, France
Received 6 March 2000; accepted 25 May 2000
AbstractÐA short and general synthesis for the preparation of various conformationally constrained b-substituted tryptophans has been
elaborated starting from indole, aldehydes and Meldrum's acid by using trimolecular condensation and Curtius rearrangement mediated
functional group transformations followed by deprotections, as key-steps. The relative con®gurations of the two diastereomeric series have
been determined indirectly by the measurement of 3J coupling constants in the corresponding tetrahydro-b-carbolines, and further supported
by means of molecular modelizations. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
present in some natural products, such as the antimicrobial
telomycine,6 the antimicrobial and antitumoral strepto-
nigrine,7 or the antitumoral alkaloid lavendamycine.8
Replacement of amino acids by their conformationally
constrained non-natural analogs in peptides has become a
versatile tool in the study of peptide±receptor relation-
ships.1 The relatively good correlation found between the
conformational properties of individual amino acid residues
and the secondary structure of peptides2 containing them has
stimulated molecular modeling studies, conformational
analyses, rational design and synthetic efforts of such non-
natural amino acids.3
Since the pioneering work of Snyder9 on the synthesis of
b-methyltryptophan, synthetic efforts for the preparation of
other b-substituted tryptophans have been stimulated by
medicinal and/or natural product chemistry applications.
Later on, Snyder's ®rst `gramine chemistry' method was
improved by using nitroacetates as nucleophiles10 allowing
the preparation of structurally diversi®ed b-substituted
tryptophan analogs implied in the synthesis of b-carboline
derivatives.11 Other improvements,12 including the devel-
opment of enantioselective versions13 have also been
achieved, mainly for the preparation of b-methyl-
tryptophans, by using chiral auxiliaries13a and/or organo-
cuprates,13a,b however, these methods also required indole
nitrogen protections. Recently, novel approaches have been
described for the synthesis of b,b-cyclized tryptophans,14
b-tri¯uoromethyl-N-acetyl-,15 and other b-substituted
tryptophan derivatives.16 Nonetheless, despite the numerous
efforts outlined above, a general and convenient procedure
leading to structurally diversi®ed b-substituted tryptophans
still remained a challenge.
Among the proteinogenic a-amino acids subjected to struc-
tural modi®cations tryptophan occupies a special position
owing to its presence in various biologically active
peptides,4 as well as due to detailed conformational studies
of b-methyl(phenyl)tryptophan isomers. For example, in
the frame of the re®nement of structure±activity relation-
ships, incorporation of the four b-methyltryptophan isomers
of different conformational pro®le revealed how topo-
graphical modi®cations of peptides were able to in¯uence
ligand±receptor interactions leading to signi®cant differ-
ences in potency and selectivity.5 Finally, the simplest
b-substituted analog, the b-methyltryptophan core is also
Keywords: b-substituted tryptophan; constrained conformation; Meldrum's
acid.
* Corresponding author. Tel.: 133-326-913589; fax: 133-326-918025;
Results and Discussion
e-mail: jy.laronze@univ-reims.fr
In order to keep up with this challenge, we have elaborated a
novel method17 based on an entirely different approach
towards b-substituted tryptophan derivatives from those
known in the literature. Herein we disclose this general
method in full detail with some re®nements compared to
²
Ã
Â
Â
Â
`Maõtre des conferences associe' at the Universite de Reims Champagne-
Ardenne (1996±1999); present address: The Skaggs Institute for Chemical
Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, CA 92037, USA.
³
Present address: Peptisyntha RD, B-1120 Bruxelles, Belgium.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00446-4

5480
C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
Scheme 1.
the preliminary version, leading to various conformationally
constrained b-substituted tryptophans. Our strategy is based
on selective functional group transformations on the
Meldrum's acid core of the trimolecular adducts, as
depicted in Scheme 1.
showed that only low diastereoselectivity,20 if any, could
be achieved during the ring opening (maximum d.e. 40%
for 3f). It is worth noting that these reactions should be
carried out carefully, due to the potential decarboxylation
of hemiacid esters 3 formed.
In the ®rst step the trimolecular condensation of unprotected
indoles 1 with various aldehydes and Meldrum's acid,18
according to Yonemitsu conditions,19 smoothly gave
adducts 2 in high yields. The unique 1,3-dioxane-4,6-
dione appendage of adducts 2 seemed to be convenient for
further functional group transformations, as by alcoholysis
it could be transformed into hemiacid esters 3. The ester
function of these latter could be regarded as the esteri®ed
acid functionality of a tryptophan, while the carboxylic
group could be transformed into an amino group.
For the transformation of hemiacid esters 3 into carbamates
5 the classical Curtius rearrangement mediated one-pot
procedure has been envisaged. Treatment of hemiacid esters
3 with diphenylphosphoryl azide (DPPA21) led to the corre-
sponding acylazides, which were subjected to a Curtius
rearrangement to afford isocyanates 4. Isocyanate inter-
mediates 4 were then transformed into carbamate esters 5
by the addition of benzyl alcohol to obtain the latter in high
yields. At this phase we tried to separate the diastereomers
of carbamate esters 5, which was successful for compounds
5a, 5b and 5g. We have to note that from this point in our
reaction sequence, a different route from the one detailed
below could be followed in favor of peptide chemistry
applications. Namely, the tert-butyl ester function of
carbamate esters 5 can be selectively cleaved, and the result-
ing Z-protected amino acids could be useful in peptide
syntheses.
Accordingly, treatment of adducts 2 with tert-butanol
afforded hemiacid esters 3 as a mixture of diastereomers.
Since for structure±activity relationship studies in peptides
all diastereomeric b-substituted tryptophans were needed, it
was useless to continue to seek by all means for diastereo-
selectivity. Otherwise, examination of Dreiding models

C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
5481
The fourth step of our synthesis consists of the debenzyl-
ation of carbamate esters 5 by catalytic hydrogenation to
afford amino esters 6. We had to do this reaction for two
reasons. On the one hand, we could separate the formerly
unseparable diastereomers at the amino ester phase in the
case of 6c, 6e and 6f, but unfortunately, we did not succeed
with amino ester 6d. On the other hand, however, it was
necessary to have amino esters 6 for the determination of the
relative con®guration of the diastereomers.
various acids in various quantities, we found that the most
advantageous way was to add no acid to the solutions of
amino esters 6 and cyclohexanone in re¯uxing dry toluene.
With this method, although the reactions sometimes
became considerably slower, we could avoid the undesired
epimerization.
The determination of the relative con®gurations is based on
the measurement of the coupling constant values between
the protons at positions 3 and 4 of the tetrahydro-b-carbo-
line ring. As shown in Table 1, the coupling constants
obtained are in good accordance with the expected values
(3Jtransˆ9±10 Hz, 3Jcisˆ3±4.5 Hz), nevertheless, the
For the ®nal deprotection of tert-butyl esters 6 the well-
known tri¯uoroacetic acid assisted method could be
proposed, but we preferred using boron tribromide, since
by this method both the carbamate and the ester functions
could be simultaneously cleaved. Thus, diastereomerically
pure carbamate esters 5 (except for the unseparable 5d, R:
cyclohexyl) or amino esters 6 (except for 6f) were treated
with 1 M boron tribromide solution in dichloromethane to
afford the appropriate b-substituted tryptophans 7, as hydro-
bromide salts, in almost quantitative yields. As for the
exceptions, b-cyclohexyl tryptophan 7d was obtained as a
diastereomeric mixture, while in the case of amino ester 6f
we had to apply tri¯uoroacetic acid for the deprotection, as
with boron tribromide O-demethylation also took place.
3
relatively low Jtrans couplings for tetrahydro-b-carbolines
8b,c suggested us that we should seek further evidence to
this con®guration assignment by molecular modelizations.
Computational methods and results23
The coupling constant values between protons 3-H and 4-H
of tetrahydro-b-carbolines 8 were determined for both
enantiomeric pairs of each compound by following the
protocol below [the calculations were executed on a Silicon
Graphics Octane (R10000/225 MHz) computer].
Relative con®guration determination
Conformational analysis. By means of exploring the
potential energy surface for each molecule, we performed
a conformational analysis using a combined method of
molecular dynamics simulations and minimizations. For
this purpose, we utilized the Discoverw24 program with
the CFF9125 force®eld by MSI. Of the numerous conforma-
tions obtained we kept those with the lowest energies, in an
interval of 40 kJ.
In order to determine the relative con®guration of the
diastereomers, we performed a Pictet±Spengler cyclization
on amino esters 6 with cyclohexanone to afford tetrahydro-
b-carbolines 8 (Table 1). In these cyclizations from one
series of diastereomers we should get cis-tetrahydro-b-
carbolines, while the other series should afford trans-tetra-
hydro-b-carbolines. Formerly we applied22 the same Pictet±
Spengler cyclization with cyclohexanone for the synthesis
of tetrahydro-b-carbolines, in the presence of acetic acid. In
our present study, however, the use of the same method
turned out to be problematic. We noticed that in most
cases the application of acetic acid led to epimerization on
the C-3 center, which rendered the con®guration assign-
ment unreliable. Finally, after several attempts to utilize
Quantumchemical minimizations. On the sample of
conformers selected in the previous step, we carried out a
second energy minimization by means of semiempirical
AM126 calculations with the Gaussian9827 program.
These computations allowed us to have a better energy
classi®cation of the conformers, of which we now kept
those of the lowest energies, in an interval of 10 kJ.
Table 1. Determination of the relative con®guration of the diastereomers: Pictet±Spengler cyclization of amino esters 6 to tetrahydro-b-carbolines 8
Tetrahydro-b-carboline
R
Reaction time (h)
Yield (%)
3Jexp (Hz)
3Jth (Hz)
cis-(3Sp,4Rp)-8a
trans-(3Sp,4Sp)-8a
cis-(3Sp,4Rp)-8b
trans-(3Sp,4Sp)-8b
cis-(3Sp,4Rp)-8c
trans-(3Sp,4Sp)-8c
cis-(3Sp,4Rp)-8e
trans-(3Sp,4Sp)-8e
cis-(3Sp,4Sp)-8f
Me
3.5
24
1.5
8
90
63
90
65
98
71
90
89
88
85
4.0
9.4
3.5
5.8
3.8
6.6
4.5
9.8
4.8
9.1
2.5
10.7
2.7
6.2
4.2
5.7
2.4
9.4
2.5
7.0
i-Pr
3-pentyl
Ph
5
4.5
10
7
7
5
2,5-diOMe-Ph
trans-(3Sp,4Rp)-8f

5482
C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
Calculation of the coupling constants 3Ji. For each
conformer i selected, we calculated the coupling constant
values between protons 3-H and 4-H of tetrahydro-b-carbo-
lines 8. For this purpose we used the Geomos28 program.
General procedure for the trimolecular condensation of
indoles 1 with aldehydes and Meldrum's acid
To a solution of indole 1 (2.50±5.00 g, 15.3±42.7 mmol)
and Meldrum's acid (2.65±6.15 g, 18.4±42.7 mmol, 1.0±
1.2 equiv.) in MeCN (30±50 mL) distilled aldehyde
(42.4±85.4 mmol, 1.0±3.0 equiv.) and a catalytic amount
of d,l-proline (0.05 equiv.) were added. After stirring at
room temperature for 6±24 h, the solvent was evaporated
under reduced pressure and the residue was puri®ed by
crystallization or by column chromatography to give the
corresponding adducts 2a±g.
Calculation of the global theoretical coupling constant
values Jth. On the basis of the previous computations, by
knowing the statistical occurence of each conformer in the
3
sample and its coupling constant value 3Ji, it was possible to
determine the global coupling constant value Jth.
3
The experimental (3Jexp) and the theoretical (3Jth) coupling
constant values are shown in Table 1. It can be seen that the
two values for the same diastereomeric racemates are in
good coherence with one another. To our contentment, the
best results were obtained in the case of tetrahydro-b-carbo-
lines 8b,c, for which compounds we were not totally certain
about our con®guration assignment, due to the relatively
5-[1-(Indol-3-yl)-ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione
(2a). From indole: 5.00 g (42.7 mmol), Meldrum's acid:
6.15 g (42.7 mmol), acetaldehyde: 3.75 g (85.4 mmol),
MeCN: 50 mL, stirring: 16 h, crystallization: ether. Yield:
10.18 g (83%); mp 130±1328C; IR (KBr) 3414, 3057, 1778,
1744 cm21; 1H NMR (CDCl3) d 1.33 (3H, s), 1.57 (3H, s),
1.64 (3H, d, Jˆ7.8 Hz), 3.80 (1H, d, Jˆ2.9 Hz), 4.34 (1H,
dq, Jˆ7.8, 2.9 Hz), 7.05±7.19 (3H, m), 7.28 (1H, dd, Jˆ8.1,
1.0 Hz), 7.63 (1H, dd, Jˆ8.1, 1.0 Hz), 8.30 (1H, brs); 13C
NMR (CDCl3) d 18.1, 27.5, 27.9, 31.0, 51.4, 104.9, 111.2,
116.1, 118.4, 119.5, 121.9, 123.3, 126.1, 135.6, 165.2,
165.5; MS (EI) m/z 287 (M1), 170, 144; HRMS calcd for
C16H17NO4 287.1158. Found 287.1178. Anal. Calcd for
C16H17NO4: C, 66.88; H, 5.96; N, 4.88. Found: C, 67.16;
H, 5.67; N, 5.07.
3
low difference between the respective experimental Jtrans
and Jcis values.
3
Despite the slight discrepancies, these results are rather
satisfactory, and the good accordance between the experi-
mental and theoretical coupling constant values permits
the differentiation between the trans and cis isomers
with no ambiguity, giving credence to our con®guration
assignment.
5-[1-(Indol-3-yl)-2-methylpropyl]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (2b). From indole: 5.00 g (42.7 mmol),
Meldrum's acid: 6.15 g (42.7 mmol), isobutyraldehyde:
6.16 g (85.4 mmol), MeCN: 50 mL, stirring: 24 h, crystal-
lization: hexane/ether 1:1. Yield: 10.36 g (77%); mp 130±
Conclusion
In summary, we have developed a short, convenient pro-
cedure for the preparation of various conformationally
constrained b-substituted tryptophans which, after con-
venient protections depending on the coupling strategy to
be used, and resolution,29 could be incorporated into divers
peptides as well as used in combinatorial libraries. Addi-
tionally, the spatially well-de®ned b-substitution patterns
would be of great value for further conformational property
studies by means of the explorations of x-space3b and other
intramolecular interactions (hydrogen bonding, van der
Waals, etc.). Both synthetic applications and conforma-
tional analyses of b-substituted tryptophans 7 are in
progress.
1
1318C; IR (KBr) 3414, 2965, 1738, 1292 cm21; H NMR
(CDCl3) d 0.82 (3H, d, Jˆ5.9 Hz), 1.08 (3H, s), 1.19 (3H, d,
Jˆ5.9 Hz), 1.58 (3H, s), 2.78 (1H, m), 3.76 (1H, brd,
Jˆ11.3 Hz), 3.92 (1H, brs), 7.00±7.22 (3H, m), 7.32 (1H,
d, Jˆ7.7 Hz), 7.70 (1H, d, Jˆ7.7 Hz), 8.21 (1H, brs); 13C
NMR (CDCl3) d 21.5, 21.8, 27.9, 28.2, 30.8, 48.8, 105.2,
110.9, 115.1, 119.5, 119.8, 122.2, 123.1, 127.3, 135.5,
165.8, 166.6; MS (EI) m/z 315 (M1), 172, 170; HRMS
calcd for C18H21NO4 315.1471. Found 315.1475. Anal.
Calcd for C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found:
C, 68.43; H, 7.02; N, 4.50.
5-[2-Ethyl-1-(indol-3-yl)-butyl]-2,2-dimethyl-1,3-dioxane-
4,6-dione (2c). From indole: 5.00 g (42.7 mmol),
Meldrum's acid: 6.15 g (42.7 mmol), 2-ethylbutyraldehyde:
8.54 g (85.4 mmol), MeCN: 50 mL, stirring: 16 h, crystal-
lization: hexane/CH2Cl2, 4:1. Yield: 12.01 g (82%); mp
Experimental
Melting points were determined on a Reichert Thermovar
hot-stage apparatus and are uncorrected. IR spectra were
measured with a BOMEM FTIR instrument. 1H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were recorded
on a Brucker AC 300 spectrometer using TMS as internal
standard. Mass spectra were recorded with VG Autospec
(EI, 70 eV) and Finnigen TSQ 700 (ESI) apparatuses. All
solvents were puri®ed by following standard literature
methods. Column chromatography was performed on
Kieselgel 60 (0.063±0.200 mm, Merck). Separations with
Chromatotronw or on preparative TLC plates were effected
on Kieselgel 60 PF254 (Merck). Reactions were monitored
using Merck TLC aluminium sheets (Kieselgel 60 F254).
1
128±1298C; IR (®lm) 3414, 1736 cm21; H NMR (CDCl3)
d 0.70 (3H, t, Jˆ7.0 Hz), 0.87 (3H, s), 1.00 (3H, t,
Jˆ7.0 Hz), 1.11 (2H, m), 1.30 (2H, m), 1.45 (3H, s), 2.50
(1H, m), 3.70 (1H, d, Jˆ3.0 Hz), 4.00 (1H, dd, Jˆ11.1,
3.0 Hz), 7.00±7.20 (5H, m), 8.20 (1H, brs); 13C NMR
(CDCl3) d 8.6, 9.9, 21.4, 21.6, 27.6, 28.1, 40.4, 40.6, 48.1,
105.2, 110.9, 114.7, 119.3, 119.6, 121.3, 121.9, 127.2,
135.4, 165.6, 167.0; MS (EI) m/z 287, 245, 199; HRMS
calcd for C20H25NO4 343.1784. Found: 343.1788. Anal.
Calcd for C20H25NO4: C, 69.95; H, 7.34; N, 4.08. Found:
C, 70.03; H, 7.26; N, 3.91.

C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
5483
5-[Cyclohexyl-(indol-3-yl)-methyl]-2,2-dimethyl-1,3-diox-
ane-4,6-dione (2d). From indole: 2.50 g (21.4 mmol),
Meldrum's acid: 3.38 g (23.5 mmol), cyclohexanecarboxal-
dehyde: 5.46 g (47.1 mmol), MeCN: 30 mL, stirring: 6 h,
chromatography: CH2Cl2/MeOH 99:1. Yield: 5.69 g
(EI) m/z 367/365 (M1), 281/279, 265/263, 224/222. Anal.
Calcd for C16H16BrNO4: C, 52.48; H, 4.40; N, 3.82. Found:
C, 52.19; H, 4.48; N, 3.76.
General procedure for the preparation of hemiacid
esters 3a±g
1
(75%); viscous oil; IR (®lm) 3414, 1738 cm21; H NMR
(CDCl3) d 1.05 (3H, s), 1.10±1.42 (5H, m), 1.52 (3H, s),
1.61±2.05 (5H, m), 2.40 (1H, m), 3.88 (1H, dd, Jˆ11.4,
2.7 Hz), 4.02 (1H, d, Jˆ2.7 Hz), 7.08±7.20 (3H, m), 7.35
(1H, d, Jˆ8.6 Hz), 7.72 (1H, d, Jˆ8.6 Hz), 8.15 (1H, brs);
13C NMR (CDCl3) d 25.6, 26.0, 27.2, 27.6, 31.7, 39.6, 43.1,
47.8, 105.0, 110.9, 114.8, 119.1, 119.3, 121.7, 123.0, 127.2,
135.3, 165.7, 166.5; MS (EI) m/z 355 (M1), 212, 170, 130.
Anal. Calcd for C21H25NO4: C, 70.96; H, 7.09; N, 3.94.
Found: C, 71.21; H, 7.26; N, 3.90.
Adducts 2a±g (0.300±10.19 g, 0.86±29.2 mmol) were
dissolved in a mixture of pyridine (1±27 mL) and the appro-
priate dry alcohol (5±100 mL), and were heated under
re¯ux for 1±3 h. After evaporation of the solvent under
reduced pressure, the residue was dissolved in CH2Cl2,
then washed at 08C with 5% citric acid and water. The
organic phase was dried over MgSO4 and evaporated to
dryness. Crystallization or column chromatography of the
residue gave hemiacid esters 3a±g as diastereomeric
mixtures.30
5-[(Indol-3-yl)-phenylmethyl]-2,2-dimethyl-1,3-dioxane-
4,6-dione (2e). From indole: 5.00 g (42.7 mmol),
Meldrum's acid: 6.15 g (42.7 mmol), benzaldehyde:
9.05 g (85.4 mmol), MeCN: 50 mL, stirring: 16 h, crystal-
lization: ether. Yield: 14.14 g (95%); mp 175±1768C; IR
(KBr) 3404, 3140, 1780, 1749 cm21; 1H NMR (DMSO-d6)
d 1.57 (3H, s), 1.84 (3H, s), 5.20 (1H, brs), 5.52 (1H, brs),
6.95 (1H, t, Jˆ8.2 Hz), 7.10 (1H, t, Jˆ8.2 Hz), 7.15±7.50
(8H, m), 10.97 (1H, brs); 13C NMR (DMSO-d6) d 26.7,
27.9, 40.2, 51.8, 105.1, 111.6, 113.4, 118.7, 118.8, 121.3,
124.2, 126.5, 127.9, 128.4, 129.0, 136.0, 141.4, 165.2,
165.7; MS (EI) m/z 349 (M1), 247, 206, 174; HRMS
calcd for C21H19NO4 349.1314. Found: 349.1323. Anal.
Calcd for C21H19NO4: C, 72.19; H, 5.48; N, 4.01. Found:
C, 71.80; H, 5.27; N, 3.91.
(2Sp,3Rp)- and (2Sp,3Sp)-2-tert-Butoxycarbonyl-3-(indol-
3-yl)-butyric acid (3a). From 2a: 4.02 g (14.0 mmol),
pyridine: 15 mL, tert-butyl alcohol: 60 mL, re¯ux: 1.5 h,
chromatography: CH2Cl2/MeOH 98:2. Yield: 3.51 g
(83%); viscous oil; IR (®lm) 3412, 2978, 1724 (br) cm21
;
1H NMR (CDCl3) d 1.03 (1.41) (9H, s), 1.43 (3H, d,
Jˆ7.2 Hz), 3.80 (2H, m), 6.86 (1H, m), 7.00±7.15 (2H,
m), 7.23 (1H, t, Jˆ7.9 Hz), 7.62 (1H, d, Jˆ7.9 Hz), 8.28
(8.32) (1H, brs), 9.41 (1H, brs); 13C NMR (CDCl3) d 19.1
(19.9), (27.1) 27.6, 31.8 (32.2), 58.8 (59.3), (82.1) 82.5,
(111.2) 111.3, (116.8) 117.1, 118.8 (118.8), 118.9 (118.9),
(119.0) 119.1, (121.6) 121.8, 126.0 (126.1), 136.1 (136.1),
168.3 (168.4), 173.4 (173.5) (Signals in brackets belong to
the same diastereomer); MS (EI) m/z 303 (M1), 245, 224;
HRMS calcd for C17H21NO4 303.1471. Found: 303.1469.
Anal. Calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62.
Found: C, 67.06; H, 6.90; N, 4.65.
5-[(2,5-Dimethoxyphenyl)-(indol-3-yl)-methyl]-2,2-dimethyl-
1,3-dioxane-4,6-dione (2f). From indole: 5.00 g (42.7
mmol), Meldrum's acid: 6.15 g (42.7 mmol), 2,5-
dimethoxybenzaldehyde: 7.10 g (42.7 mmol), MeCN:
50 mL, stirring: 15 h, crystallization: ether. Yield: 15.01 g
(86%); mp 138±1398C; IR (KBr) 3401, 2947, 1782,
(2Sp,3Rp)- and (2Sp,3Sp)-2-tert-Butoxycarbonyl-3-(indol-
3-yl)-4-methylpentanoic acid (3b). From 2b: 9.20 g
(29.2 mmol), pyridine: 18 mL, tert-butyl alcohol: 60 mL,
re¯ux: 1 h, crystallization: hexane/ether 3:2. Yield: 7.91 g
(82%); mp 171±1738C; IR (KBr) 3437, 2968, 1740,
1
1744 cm21; H NMR (CDCl3) d 1.60 (3H, s), 1.65 (3H,
s), 3.55 (3H, s), 3.85 (3H, s), 4.46 (1H, d, Jˆ3.4 Hz), 5.76
(1H, d, Jˆ3.4 Hz), 6.67±6.82 (3H, m), 7.04 (1H, t,
Jˆ8.2 Hz), 7.12 (1H, t, Jˆ8.2 Hz), 7.23 (1H, d,
Jˆ2.7 Hz), 7.28 (1H, d, Jˆ8.2 Hz), 7.52 (1H, d,
Jˆ8.2 Hz), 8.32 (1H, brs); 13C NMR (CDCl3) d 27.5,
28.1, 35.7, 50.6, 55.2, 55.6, 104.6, 110.6, 111.1, 111.6,
114.3, 118.2, 119.0, 119.5, 122.2, 123.7, 127.3, 129.7,
135.8, 150.6, 153.3, 165.0, 165.6; MS (EI) m/z 409 (M1),
323, 307, 292; 279, 266; HRMS calcd for C23H23NO6
409.1525. Found: 409.1543. Anal. Calcd for C23H23NO6:
C, 67.47; H, 5.66; N, 3.42. Found: C, 67.10; H, 5.49; N,
3.38.
1686 cm21
;
1H NMR (DMSO-d6)
d
0.78 (3H, d,
Jˆ5.9 Hz), 0.83 (3H, d, Jˆ5.9 Hz), 0.89 (9H, s), 2.03
(1H, m), 3.58±3.68 (1H, m), 3.73±3.83 (1H, m), 6.98
(1H, t, Jˆ7.7 Hz), 7.05 (1H, t, Jˆ7.7 Hz), 7.12 (7.19)
(1H, brs), 7.32 (1H, d, Jˆ7.7 Hz), 7.57 (1H, d, Jˆ7.7 Hz),
10.90 (1H, brs), 12.70 (1H, brs); 13C NMR (DMSO-d6) d
17.4 (17.4), 22.2 (22.3), 27.0 (27.7), 29.9 (29.9), (41.2) 41.4,
(57.2) 57.5, 80.1 (81.1), 111.3 (111.3), 111.5 (111.8), 118.3
(118.4), (119.2) 119.3, 120.7 (120.7), (123.7) 124.0, 128.8
(128.8), 135.8 (135.8), 167.3 (168.2), (169.4) 170.3 (Signals
in brackets belong to the same diastereomer); MS (EI) m/z
331 (M1), 188, 172, 170; HRMS calcd for C19H25NO4
331.1784. Found: 331.1810. Anal. Calcd for C19H25NO4:
C, 68.86; H, 7.60; N, 4.22. Found: C, 69.10; H, 7.63; N,
4.15.
5-[1-(5-Bromoindol-3-yl)-ethyl]-2,2-dimethyl-1,3-dioxane-
4,6-dione (2g). From 5-bromoindole: 3.00 g (15.3 mmol),
Meldrum's acid: 2.64 g (18.36 mmol), acetaldehyde: 2.02 g
(45.9 mmol), MeCN: 40 mL, stirring: 12 h, chromato-
graphy: hexane/acetone 8:2. Yield: 4.21 g (75%); viscous
oil; IR (®lm) 3416, 2944, 1761, 1734 cm21 1H NMR
;
(2Sp,3Rp)- and (2Sp,3Sp)-2-tert-Butoxycarbonyl-4-ethyl-
3-(indol-3-yl)-hexanoic acid (3c). From 2c: 10.02 g
(29.2 mmol), pyridine: 18 mL, tert-butyl alcohol: 60 mL,
re¯ux: 1.5 h, crystallization: hexane/ether 1:2. Yield:
7.26 g (69%); mp 180±1818C; IR (KBr) 3441, 2967,
(CDCl3) d 1.45 (3H, s), 1.65 (3H, d, Jˆ7.3 Hz), 1.70 (3H,
s), 3.79 (1H, d, Jˆ2.7 Hz), 4.27 (1H, dq, Jˆ2.7, 7.3 Hz),
7.18±7.30 (3H, m), 7.79 (1H, s), 8.50 (1H, brs); 13C NMR
(CDCl3) d 17.9, 27.5, 28.3, 30.5, 51.4, 104.9, 112.7, 112.9,
116.1, 121.1, 124.9, 125.5, 128.1, 134.2, 164.7, 165.4; MS
1734, 1713 cm21 1H NMR (DMSO-d6) d 0.85 (3H, t,
;

5484
C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
Jˆ6.8 Hz), 0.90 (1.45) (9H, s), 1.02 (3H, t, Jˆ6.8 Hz), 1.26
(2H, m), 1.40 (1H, m), 1.68 (2H, m), 3.78±3.90 (2H, m),
6.99 (1H, t, Jˆ7.7 Hz), 7.05 (1H, t, Jˆ7.7 Hz), 7.14 (7.19)
(1H, brs), 7.32 (1H, d, Jˆ7.7 Hz), 7.55 (1H, d, Jˆ7.7 Hz),
10.88 (1H, brs), 12.48 (1H, brs); 13C NMR (DMSO-d6) d
12.5 (12.5), 12.7 (12.7), 22.9 (22.9), 23.9 (23.9), 27.1 (27.7),
(37.4) 37.7, 44.4 (44.4), 57.6 (57.6), 80.0 (81.5), 111.3
(111.3), 112.2 (113.0), 118.3 (118.4), (118.9) 119.0, 120.7
(120.7), (123.5) 123.9, 128.8 (128.8), 135.7 (135.7), 167.4
(168.1), (169.3) 170.2 (Signals in brackets belong to the
same diastereomer); MS (EI) m/z 359 (M1), 200, 188,
170; HRMS calcd for C21H29NO4 359.2097. Found:
359.2100. Anal. Calcd for C21H29NO4: C, 70.17; H, 8.13;
N, 3.90. Found: C, 70.01; H, 7.96; N, 3.85.
d, Jˆ7.9 (8.0) Hz], 6.80 (7.00) [1H, t, Jˆ8.2 (8.4) Hz], 6.87
(7.06) [1H, t, Jˆ8.2 (8.4) Hz], 7.05 (7.24) [1H, d, Jˆ2.8
(2.9) Hz], 7.08 (7.28) [1H, d, Jˆ8.2 (8.4) Hz], 7.52 (7.68)
[1H, d, Jˆ8.2 (8.4) Hz], (9.41) 9.45 (1H, brs); 13C NMR
(CDCl3±DMSO-d6) d 26.7 (26.9), 35.9 (36.2), 54.7 (55.1),
55.3 (55.5), 57.0 (57.3), 80.3 (80.6), 110.4 (110.6), 110.8
(111.1), 111.2 (111.4), 115.1 (115.3), 115.6 (115.9), 117.9
(118.2), 118.5 (118.7), 120.5 (120.8), 121.0 (121.2), 126.4
(126.6), 131.0 (131.1), 135.4 (135.5), 150.7 (150.9), 152.6
(152.8), 166.6 (166.9), 169.4 (169.7) (Signals in brackets
belong to the same diastereomer); MS (EI) m/z 425 (M1),
381, 325, 306, 266, 250, 236; HRMS calcd for C24H27NO6
425.1838. Found: 428.1839. Anal. Calcd for
C24H27NO6´0.25H2O: C, 67.04; H, 6.45; N, 3.26. Found:
C, 67.09; H, 6.15; N, 3.20.
(2Sp,3Rp)- and (2Sp,3Sp)-2-tert-Butoxycarbonyl-3-cyclo-
hexyl-3-(indol-3-yl)-propionic acid (3d). From 2d:
10.19 g (28.7 mmol), pyridine: 27 mL, tert-butyl alcohol:
100 mL, re¯ux: 2 h, chromatography: CH2Cl2/MeOH 95:5,
then crystallization: ether. Yield: 8.92 g (84%); mp 114±
(2Sp,3Rp)- and (2Sp,3Sp)-2-tert-Butoxycarbonyl-3-(5-
bromoindol-3-yl)-butyric acid (3g). From 2g: 2.93 g
(8.0 mmol), pyridine: 10 mL, tert-butyl alcohol: 50 mL,
re¯ux: 2 h, chromatography: hexane/acetone 7:3. Yield:
2.30 g (75%); viscous oil; IR (®lm) 3397, 2966, 1738,
1
1168C; IR (KBr) 3412, 2928, 1720, 1705 cm21; H NMR
1
(DMSO-d6) d 0.63±1.28 (5H, m) 1.43 (9H, brs), 1.50±1.84
(6H, m), 3.56±3.71 (1H, m), 3.81±3.95 (1H, m), 6.93±7.10
(2H, m), 7.18 (1H, brs), 7.30 (1H, d, Jˆ8.7 Hz), 7.55 (1H, d,
Jˆ8.7 Hz), 10.90 (1H, brs), 12.20 (1H, brs); 13C NMR
(DMSO-d6) d 26.1 (26.1), 26.5 (26.5), 27.1 (27.7), 32.4
(32.5), 40.6 (40.6), 41.3 (41.3), 56.6 (56.7), (80.1) 81.1,
111.3 (111.3), (112.5) 112.9, (118.3) 118.4, (119.2) 119.3,
120.7 (120.7), 123.5 (123.7), 128.7 (128.7), 135.8 (135.8),
(167.5) 168.4, 169.5 (170.4) (Signals in brackets belong to
the same diastereomer); MS (EI) m/z 371 (M1), 271, 243,
212, 188, 170; HRMS calcd for C22H29NO4 371.2097.
Found: 371.2110. Anal. Calcd for C22H29NO4´0.5H2O: C,
69.45; H, 7.95; N, 3.68. Found: C, 69.35; H, 7.69; N, 3.65.
1715 cm21; H NMR (CDCl3) d 1.11 (1.44) (9H, s), 1.47
(3H, d, Jˆ6.6 Hz), 3.67±3.82 (2H, m), 7.02 (1H, brs), 7.15±
7.28 (2H, m), 7.78 (1H, s), 8.37 (1H, brs), 9.56 (1H, brs); 13C
NMR (CDCl3) d 19.2 (19.9), (27.3) 27.8, 31.9 (32.1), 58.6
(59.1), (82.5) 82.9, 112.6 (112.6), (112.7) 112.8, (117.1)
117.3, 121.6 (121.9), 122.9 (123.1), 124.8 (124.8), 128.0
(128.1), 134.7 (134.8), 168.4 (168.5), 172.8 (172.9) (Signals
in brackets belong to the same diastereomer); MS (EI) m/z
383/381 (M1), 327/325, 283/281, 222/224. Anal. Calcd for
C17H20BrNO4: C, 53.42; H, 5.27; N, 3.66. Found: C, 53.19;
H, 5.41; N, 3.62.
General procedure for the preparation of carbamate
esters 5a±g
(2Sp,3Rp)- and (2Sp,3Sp)-2-tert-Butoxycarbonyl-3-(indol-
3-yl)-3-phenylpropionic acid (3e). From 2e: 4.89 g
(14.0 mmol), pyridine: 15 mL, tert-butyl alcohol: 60 mL,
re¯ux: 1.5 h, crystallization: ether. Yield: 3.63 g (71%);
To a suspension of hemiacid esters 3a±g (2.27±7.00 g,
5.94±19.5 mmol) in dry toluene (40±160 mL) were added
triethylamine (Et3N) (0.659±2.36 g, 0.91±3.25 mL, 6.53±
23.4 mmol, 1.1±1.2 equiv.) and diphenylphosphoryl azide
(DPPA) (2.45±5.92 g, 8.91±21.5 mmol, 1.1±1.5 equiv.).
The reaction mixture was heated at 1108C for 2 h under
nitrogen atmosphere, then benzyl alcohol (BnOH) (0.706±
2.77 g, 0.68±2.65 mL, 6.53±25.6 mmol, 1.1±1.5 equiv.)
was added and the heating was continued overnight. After
evaporation of the solvent, the residue was dissolved in
CH2Cl2 (50 mL), the solution was washed with 5% citric
acid, brine and saturated K2CO3 solution, dried over
MgSO4, and evaporated to dryness in vacuo. The residue
was submitted to ¯ash chromatography (eluent: CH2Cl2) to
give carbamate esters 5a±g.
mp 180±1828C; IR (KBr) 3437, 3412, 3133, 1724 cm21
;
1H NMR (DMSO-d6) d 1.16 (1.19) (9H, s), 4.20 (4.25)
[1H, d, Jˆ6.2 (7.1) Hz], 4.84 (4.88) [1H, d, Jˆ6.2
(7.1) Hz], 6.98±7.55 (10H, m), 10.67 (1H, brs); 13C NMR
(DMSO-d6) d 27.3 (27.3), 42.3 (42.6), 58.4 (58.5), 80.7
(80.8), 111.2 (111.2), 115.9 (116.4), 118.4 (118.6), 120.9
(121.0), (121.1) 121.4, 126.0 (126.1), 126.4 (126.5), 127.5
(127.8), 127.9 (128.0), 128.1 (128.3), (136.1) 136.2, 142.1
(142.6), 166.9 (167.0), (169.1) 169.2 (Signals in brackets
belong to the same diastereomer); MS (EI) m/z 365 (M1),
264, 246, 219, 205; HRMS calcd for C22H23NO4 365.1627.
Found: 365.1608. Anal. Calcd for C22H23NO4: C, 72.31; H,
6.34; N, 3.83. Found: C, 72.28; H, 6.14; N, 4.07.
(2Sp,3Rp)- and (2Sp,3Sp)-a-N-Benzyloxycarbonyl-b-
methyltryptophan tert-butyl ester (5a). From 3a: 3.03 g
(10.0 mmol), Et3N: 1.11 g (11.0 mmol), DPPA: 3.03 g
(11.0 mmol), BnOH: 1.30 g (12.0 mmol), toluene: 50 mL.
Yield: 3.10 g (76%). The two diastereomers were separated
by Chromatotronw (hexane/EtOAc, 1!5% of EtOAc). The
analytical samples were crystallized from ether.
(2Sp,3Rp)- and (2Sp,3Sp)-2-tert-Butoxycarbonyl-3-(2,5-
dimethoxyphenyl)-3-(indol-3-yl)-propionic acid (3f ).
From 2f: 5.72 g (14.0 mmol), pyridine: 15 mL, tert-butyl
alcohol: 60 mL, re¯ux: 1.5 h, crystallization: ether. Yield:
5.73 g (96%); mp 164±1668C; IR (KBr) 3337, 3144, 3086,
1739, 1717 cm21 1H NMR (CDCl3±DMSO-d6) d 1.03
;
(1.12) (9H, s), 3.53 (3.70) (3H, s), 3.64 (3.80) (3H, s),
4.21 (4.43) (1H, d, Jˆ11.4 Hz), 5.18 (5.32) (1H, d,
Jˆ11.4 Hz), (6.44) 6.73 [1H, d, Jˆ(3.1) 3.1 Hz], 6.45
(6.60) [1H, dd, Jˆ7.9, 3.1 (8.0, 3.1) Hz], 6.55 (6.72) [1H,
(2Sp,3Rp)-5a: mp 114.5±115.58C (ether); IR (KBr) 3408,
1
3364, 2979, 1709 cm21; H NMR (CDCl3) d 1.31 (9H, s),
1.42 (3H, d, Jˆ7.2 Hz), 3.70 (1H, m), 4.59 (1H, dd, Jˆ4.5,

C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
5485
8.6 Hz), 5.10 (2H, s), 5.36 (1H, d, Jˆ8.6 Hz), 6.92 (1H, brs),
7.05±7.39 (8H, m), 7.72 (1H, d, Jˆ8.1 Hz), 8.27 (1H, brs);
13C NMR (CDCl3) d 18.0, 27.8, 33.8, 59.2, 66.8, 82.0,
111.1, 116.0, 119.3, 119.4, 121.5, 122.0, 126.6, 128.0,
128.1, 128.5, 136.1, 136.2, 156.2, 170.7; MS (EI) m/z 408
(M1), 335, 307, 261, 244; HRMS calcd for C24H28N2O4
408.2049. Found: 408.2030. Anal. Calcd for C24H28N2O4:
C, 70.57; H, 6.91; N, 6.86. Found: C, 70.47; H, 6.91; N, 6.88.
(21.45 mmol), BnOH: 2.74 g (25.35 mmol), toluene:
160 mL. Yield: 7.82 g (86%); viscous oil; IR (®lm) 3412,
1
3352, 2965, 1719 cm21; H NMR (CDCl3) d 0.68±0.80
(3H, m), 0.91±1.02 (3H, m), 1.15 (1.29) (9H, s), 1.40±
1.59 (4H, m), 1.80 (1H, m), 3.37 (3.53) [1H, t, Jˆ6.8 Hz
(dd, Jˆ4.1, 9.5 Hz)], 4.68±4.83 (1H, m), 5.03±5.23 (3H,
m), (6.91) 6.94 [1H, (brs) d, Jˆ1.8 Hz], 7.06±7.39 (8H,
m), 7.54 (7.61) (1H, d, Jˆ7.7 Hz), 8.29 (1H, brs); 13C
NMR (CDCl3) d 9.4 (11.3), 10.4 (10.8), 21.3 (22.3), 22.0
(22.7), (27.6) 27.8, (40.8) 41.6, 41.3 (41.9), 56.2 (56.7), 66.8
(66.8), (81.5) 81.8, (110.9) 111.1, (112.7) 113.1, 119.2
(119.6), (119.3) 119.7, (121.7) 121.9, 122.3 (122.7),
(126.9) 127.9, 127.6 (128.1), 128.0 (128.4), 128.7 (128.8),
(135.5) 136.0, 136.4 (136.4), (155.7) 156.5, (171.5) 172.9
(Signals in brackets belong to the same diastereomer); MS
(EI) m/z 464 (M1), 200, 130; HRMS calcd for C28H36N2O4
464.2675. Found: 464.2675. Anal. Calcd for C28H36N2O4:
C, 72.39; H, 7.81; N, 6.03. Found: C, 72.15; H, 7.99; N,
6.11.
(2Sp,3Sp)-5a: mp 119±1208C (ether); IR (KBr) 3410, 3354,
1
2976, 1712 cm21; H NMR (CDCl3) d 1.28 (9H, s), 1.40
(3H, d, Jˆ7.9 Hz), 3.55 (1H, m), 4.62 (1H, dd, Jˆ4.2,
8.5 Hz), 5.05 (2H, m), 5.35 (1H, d, Jˆ8.5 Hz), 6.92 (1H,
brs), 7.04±7.38 (8H, m), 7.63 (1H, d, Jˆ8.1 Hz), 8.19 (1H,
brs); 13C NMR (CDCl3) d 16.9, 27.7, 34.2, 59.2, 66.8, 81.7,
111.2, 116.5, 119.1, 119.3, 121.5, 121.9, 126.7, 127.8,
128.0, 128.4, 136.1, 136.2, 156.0, 170.9; MS (EI) m/z 408
(M1), 335, 307, 261, 244; HRMS calcd for C24H28N2O4
408.2049. Found: 408.2038. Anal. Calcd for C24H28N2O4:
C, 70.57; H, 6.91; N, 6.86. Found: C, 70.22; H, 6.76; N,
6.79.
(2Sp,3Rp)- and (2Sp,3Sp)-a-N-Benzyloxycarbonyl-b-
cyclohexyltryptophan tert-butyl ester (5d). From 3d:
5.42 g (14.6 mmol), Et3N:1.77 g (17.52 mmol), DPPA:
4.42 g (16.06 mmol), BnOH: 2.36 g (21.9 mmol), toluene:
70 mL. Yield: 6.07 g (87%); viscous oil; IR (®lm) 3412,
(2Sp,3Rp)- and (2Sp,3Sp)-a-N-Benzyloxycarbonyl-b-
isopropyltryptophan tert-butyl ester (5b). From 3b:
6.45 g (19.5 mmol), Et3N: 2.36 g (23.4 mmol), DPPA:
5.90 g (21.45 mmol), BnOH: 2.74 g (25.35 mmol), toluene:
160 mL. Yield: 7.41 g (87%). The two diastereomers were
separated by repeated fractional crystallizations (hexane/
ether, 3:2).
1
3358, 2986, 1724 cm21; H NMR (CDCl3) d 0.70±1.18
(5H, m), 1.22 (1.28) (9H, s), 1.47±1.90 (5H, m), 2.05
(2.20) (1H, m), 3.15 (3.30) [1H, t, Jˆ7.0 Hz (dd, Jˆ4.4,
9.1 Hz)], 4.75±4.92 (1H, m), 5.01±5.28 (3H, m), 6.93
(1H, brs), 7.04±7.40 (8H, m), 7.54 (7.60) (1H, d,
Jˆ7.8 Hz), (8.12) 8.17 (1H, brs); 13C NMR (CDCl3) d
26.1 (26.4), (27.7) 27.9, (30.3) 30.6, 31.7 (32.0), 39.1
(39.6), 45.4 (45.6), (55.7) 56.1, 66.8 (66.8), (81.5) 81.8,
110.9 (111.3), (113.1) 113.4, 119.4 (119.7), (119.6) 119.9,
(121.9) 122.3, (122.0) 122.1, 127.8 (127.8), 127.9 (127.9),
128.1 (128.1), 128.5 (128.5), (135.6) 136.2, (135.7) 136.0,
(155.9) 156.4, (172.1) 172.9 (Signals in brackets belong to
the same diastereomer); MS (EI) m/z 476 (M1), 401, 360,
212, 181, 130. Anal. Calcd for C29H36N2O4: C, 73.08; H,
7.61; N, 5.88. Found: C, 72.85; H, 7.50; N, 5.85.
(2Sp,3Rp)-5b: mp 117±1188C; IR (KBr) 3427, 3352, 2965,
1
1705 cm21; H NMR (CDCl3) d 0.88 (3H, d, Jˆ5.9 Hz),
1.09 (3H, d, Jˆ5.9 Hz), 1.19 (9H, s), 2.25 (1H, m), 3.12
(1H, t, Jˆ8.6 Hz), 4.78 (1H, t, Jˆ8.6 Hz), 5.08 (1H, d,
Jˆ12.6 Hz), 5.17 (1H, d, Jˆ12.6 Hz), 5.19 (1H, d,
Jˆ8.6 Hz), 6.98 (1H, d, Jˆ2.3 Hz), 7.07 (1H, t,
Jˆ7.7 Hz), 7.18 (1H, t, Jˆ7.7 Hz), 7.29±7.39 (6H, m),
7.55 (1H, d, Jˆ7.7 Hz), 8.11 (1H, brs); 13C NMR (CDCl3)
d 20.0, 21.7, 27.6, 29.6, 46.7, 56.9, 66.8, 81.5, 110.9, 112.8,
119.4, 119.5, 121.9, 122.5, 128.1, 128.5, 128.8, 128.9,
135.6, 136.4, 155.7, 170.8; MS (EI) m/z 436 (M1), 173,
172, 157, 130; HRMS calcd for C26H32N2O4 436.2362.
Found: 436.2362. Anal. Calcd for C26H32N2O4: C, 71.53;
H, 7.39; N, 6.41. Found: C, 71.38; H, 7.62; N, 6.38.
(2Sp,3Rp)- and (2Sp,3Sp)-a-N-Benzyloxycarbonyl-b-
phenyltryptophan tert-butyl ester (5e). From 3e: 3.65 g
(10.0 mmol), Et3N: 1.11 g (11.0 mmol), DPPA: 3.03 g
(11.0 mmol), BnOH: 1.30 g (12.0 mmol), toluene: 50 mL.
Yield: 4.37 g (93%); viscous oil; IR (®lm) 3414, 3347,
(2Sp,3Sp)-5b: mp 132±1338C; IR (KBr) 3427, 3352, 2976,
1
1721 cm21; H NMR (CDCl3) d 0.79 (3H, d, Jˆ5.9 Hz),
1707 cm21; H NMR (CDCl3±CD3OD) d 1.15 (1.21) (9H,
1
1.19 (3H, d, Jˆ5.9 Hz), 1.28 (9H, s), 2.17 (1H, m), 3.23
(1H, dd, Jˆ4.1, 9.0 Hz), 4.82 (1H, dd, Jˆ4.1, 9.5 Hz), 5.09
(1H, d, Jˆ13.5 Hz), 5.15 (1H, d, Jˆ13.5 Hz), 5.20 (1H, d,
Jˆ9.5 Hz), 6.99 (1H, d, Jˆ1.4 Hz), 7.09 (1H, t, Jˆ7.7 Hz),
7.18 (1H, t, Jˆ7.7 Hz), 7.29±7.40 (6H, m), 7.62 (1H, d,
Jˆ7.7 Hz), 8.09 (1H, brs); 13C NMR (CDCl3) d 20.9,
21.7, 27.8, 29.6, 46.6, 56.5, 66.8, 81.9, 111.1, 113.5,
119.4, 119.8, 122.0, 122.1, 127.9, 128.0, 128.4, 128.5,
136.0, 136.4, 156.5, 171.3; MS (EI) m/z 436 (M1), 173,
172, 157, 130; HRMS calcd for C26H32N2O4 436.2362.
Found: 436.2359. Anal. Calcd for C26H32N2O4: C, 71.53;
H, 7.39; N, 6.41. Found: C, 71.44; H, 7.57; N, 6.71.
s), 4.67 (4.75) [1H, d, Jˆ9.1 (8.1) Hz], 4.91±5.12 (3H, m),
(5.73) 5.97 (1H, d, Jˆ9.0 Hz), 6.92±7.45 (15H, m), 9.72
(1H, brs); 13C NMR (DMSO-d6) d 27.3 (27.4), 44.6
(45.2), 58.7 (58.9), 65.5 (65.6), 80.2 (80.4), 111.5 (111.6),
114.4 (115.0), (118.5) 118.6, (118.8) 118.9, (121.2) 121.7,
(126.4) 126.5, 126.6 (126.9), (127.2) 127.3, 127.6 (127.7),
(127.7) 127.8, (127.9) 127.95, 128.0 (128.1), (128.3) 128.5,
(129.1) 130.3, (136.4) 137.2, (141.5) 142.8, 156.0 (156.3),
(170.9) 171.1 (Signals in brackets belong to the same dia-
stereomer); MS (EI) m/z 470 (M1), 370, 340, 279, 234, 208;
HRMS calcd for C29H30N2O4 470.2206. Found: 470.2204.
Anal. Calcd for C29H30N2O4: C, 74.02; H, 6.43; N, 5.95.
Found: C, 73.85; H, 6.45; N, 5.86.
(2Sp,3Rp)- and (2Sp,3Sp)-a-N-Benzyloxycarbonyl-b-(3-
pentyl)-tryptophan tert-butyl ester (5c). From 3c: 7.00 g
(19.5 mmol), Et3N: 2.36 g (23.4 mmol), DPPA: 5.90 g
(2Sp,3Rp)- and (2Sp,3Sp)-a-N-Benzyloxycarbonyl-b-(2,5-
dimethoxyphenyl)-tryptophan tert-butyl ester (5f). From

5486
C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
3f: 4.25 g (10.0 mmol), Et3N: 1.11 g (11.0 mmol), DPPA:
3.03 g (11.0 mmol), BnOH: 1.30 g (12.0 mmol), toluene:
50 mL. Yield: 4.76 g (90%); viscous oil; IR (®lm) 3414,
(2Sp,3Rp)- and (2Sp,3Sp)-b-Methyltryptophan tert-butyl ester
(6a). From 5a: 2.45 g (6.00 mmol), EtOH: 70 mL, AcOH:
0.54 mL, Pd/C catalyst: 0.368 g, crystallization: ether.
1
3367, 1717 cm21; H NMR (CDCl3) d 1.15 (1.18) (9H, s),
3.61 (3.64) (3H, s), 3.82 (3.85) (3H, s), 4.93±5.20 (4H, m),
(5.43) 5.58 (1H, d, Jˆ9.1 Hz), 6.62±6.83 (3H, m), 6.96±
7.52 (10H, m), (8.47) 8.52 (1H, brs); 13C NMR (CDCl3) d
27.4 (27.5), 38.1 (39.2), 55.4 (55.6), 55.7 (56.0), (57.5) 57.9,
66.6 (66.6), 81.3 (81.5), (111.0) 111.4, 111.6 (111.6), 112.0
(112.2), 114.1 (114.2), 116.1 (116.5), 118.9 (118.9), 119.2
(119.3), (121.9) 122.2, 122.9 (123.3), 127.3 (127.4), 127.7
(127.7), 127.8 (127.9), 128.3 (128.3), 129.8 (129.8), (135.9)
136.0, 136.4 (136.4), (151.4) 152.6, (153.3) 153.5, 155.8
(156.0), (170.9) 171.2 (Signals in brackets belong to the
same diastereomer); MS (EI) m/z 530 (M1), 485, 458,
430, 267. Anal. Calcd for C31H34N2O6: C, 70.17; H, 6.46;
N, 5.28. Found: C, 70.29; H, 6.66; N, 5.30.
(2Sp,3Rp)-6a: yield: 1.49 g (91%); mp 94±968C; IR (KBr)
1
3408, 3364, 2980, 1728 cm21; H NMR (CDCl3) d 1.40
(9H, s), 1.42 (3H, d, Jˆ7.7 Hz), 1.67 (2H, brs), 3.40 (1H,
dq, Jˆ7.7 Hz), 3.61 (1H, d, Jˆ7.7 Hz), 6.96 (1H, d,
Jˆ2.6 Hz), 7.04±7.18 (2H, m), 7.28 (1H, d, Jˆ8.4 Hz),
7.66 (1H, d, Jˆ8.2 Hz), 8.67 (1H, brs); 13C NMR (CDCl3)
d 18.9, 27.9, 36.4, 60.6, 81.1, 111.3, 116.8, 119.0, 119.3,
121.7, 121.8, 126.8, 136.3, 174.3; MS (EI) m/z 274 (M1),
255, 173, 158, 144; HRMS calcd for C16H22N2O2 274.1681.
Found: 274.1679. Anal. Calcd for C16H22N2O2: C, 70.01; H,
8.08; N, 10.21. Found: C, 70.12; H, 7.98; N, 10.24.
(2Sp,3Sp)-6a: yield: 1.54 g (94%); mp 97±98.58C; IR (KBr)
1
3408, 3360, 2979, 1728 cm21; H NMR (CDCl3) d 1.29
(2Sp,3Rp)- and (2Sp,3Sp)-a-N-Benzyloxycarbonyl-b-methyl-
5-bromotryptophan tert-butyl ester (5g). From 3g: 2.27 g
(5.94 mmol), Et3N: 0.66 g (6.53 mmol), DPPA: 2.45 g
(8.91 mmol), BnOH: 7.06 g (6.53 mmol), toluene: 40 mL.
Yield: 2.33 g (81%). The two diastereomers were separated
by Chromatotronw (hexane/methyl tert-butyl ether, 9:1).
(3H, d, Jˆ7.3 Hz), 1.46 (9H, s), 1.78 (2H, brs), 3.61 (1H,
m), 3.81 (1H, d, Jˆ4.5 Hz), 6.95 (1H, d, Jˆ2.5 Hz), 7.06±
7.20 (2H, m), 7.30 (1H, d, Jˆ8.9 Hz), 7.65 (1H, d,
Jˆ8.6 Hz), 8.60 (1H, brs); 13C NMR (CDCl3) d 13.6,
27.9, 34.6, 58.6, 80.9, 111.3, 117.7, 118.8, 119.1, 121.7,
121.9, 126.4, 136.4, 173.9; MS (EI) m/z 274 (M1), 255,
173, 158, 144; HRMS calcd for C16H22N2O2 274.1681.
Found: 274.1685. Anal. Calcd for C16H22N2O2: C, 70.01;
H, 8.08; N, 10.21. Found: C, 70.29; H, 8.26; N, 10.18.
(2Sp,3Rp)-5g: viscous oil; IR (®lm) 3416, 3360, 2974,
1
1712 cm21; H NMR (CDCl3) d 1.36 (9H, s), 1.42 (3H, d,
Jˆ7.2 Hz), 3.70 (1H, m), 4.58 (1H, dd, Jˆ4.6, 8.8 Hz), 5.13
(2H, s), 5.32 (1H, d, Jˆ8.8 Hz), 6.99 (1H, d, Jˆ1.9 Hz),
7.13±7.42 (7H, m), 7.85 (1H, s), 8.35 (1H, brs); 13C NMR
(CDCl3) d 18.4, 27.9, 33.6, 59.1, 67.0, 82.4, 112.6, 112.7,
115.9, 122.0, 122.7, 125.0, 128.1, 128.2, 128.3, 128.5,
134.6, 136.2, 156.3, 170.6; MS (EI) m/z 488/486 (M1),
415/413, 387/385, 341/339, 324/322. Anal. Calcd for
C24H27BrN2O4: C, 59.15; H, 5.58; N, 5.75. Found: C,
59.06; H, 5.55; N, 5.79.
(2Sp,3Rp)- and (2Sp,3Sp)-b-Isopropyltryptophan tert-
butyl ester (6b). From 5b: 7.33 g (16.8 mmol), EtOH:
120 mL, AcOH: 1.15 mL, Pd/C catalyst: 1.83 g, crystalliza-
tion: hexane/ether 10:1.
(2Sp,3Rp)-6b: yield: 4.88 g (96%); mp 141±1438C; IR (KBr)
1
3364, 3302, 2959, 1723 cm21; H NMR (CDCl3) d 0.88
(3H, d, Jˆ5.9 Hz), 0.99 (3H, d, Jˆ5.9 Hz), 1.15 (9H, s),
1.61 (2H, brs), 2.41 (1H, m), 3.12 (1H, t, Jˆ8.1 Hz), 3.74
(1H, d, Jˆ8.1 Hz), 6.94 (1H, d, Jˆ0.9 Hz), 7.09 (1H, t,
Jˆ7.7 Hz), 7.16 (1H, t, Jˆ7.7 Hz), 7.32 (1H, d,
Jˆ7.7 Hz), 7.63 (1H, d, Jˆ7.7 Hz), 8.39 (1H, brs); 13C
NMR (CDCl3) d 19.1, 21.8, 27.8, 28.6, 47.0, 58.4, 80.5,
110.8, 114.0, 119.1, 119.5, 121.6, 122.4, 128.9, 135.6,
174.8; MS (EI) m/z 302 (M1), 201, 172, 158, 130; HRMS
calcd for C18H26N2O2 302.1994. Found: 302.1992. Anal.
Calcd for C18H26N2O2: C, 71.49; H, 8.67; N, 9.26. Found:
C, 71.62; H, 8.86; N, 9.37.
(2Sp,3Sp)-5g: viscous oil; IR (®lm) 3418, 3358, 3061, 2966
1
1713 cm21; H NMR (CDCl3) d 1.31 (9H, s), 1.37 (3H, d,
Jˆ7.0 Hz), 3.49 (1H, m), 4.57 (1H, dd, Jˆ6.0, 9.0 Hz), 5.06
(2H, s), 5.36 (1H, d, Jˆ9.0 Hz), 6.94 (1H, d, Jˆ2.1 Hz),
7.12±7.40 (7H, m), 7.76 (1H, s), 8.24 (1H, brs); 13C NMR
(CDCl3) d 16.7, 27.8, 34.2, 59.2, 66.9, 82.0, 112.6, 112.7,
116.5, 121.7, 122.8, 124.8, 127.0, 128.1, 128.4, 128.5,
134.7, 136.3, 156.0, 170.7; MS (EI) m/z 488/486 (M1),
415/413, 387/385, 341/339, 324/322. Anal. Calcd for
C24H27BrN2O4: C, 59.15; H, 5.58; N, 5.75. Found: C,
59.25; H, 5.55; N, 5.70.
(2Sp,3Sp)-6b: yield: 3.87 g (76%); mp 125±1278C; IR (KBr)
1
3381, 3171, 2974, 1725 cm21; H NMR (CDCl3) d 0.81
(3H, d, Jˆ5.9 Hz), 1.08 (3H, d, Jˆ5.9 Hz), 1.25 (9H, s),
1.67 (2H, brs), 2.19 (1H, m), 3.15 (1H, dd, Jˆ5.0,
9.0 Hz), 3.88 (1H, d, Jˆ5.0 Hz), 7.07 (1H, d, Jˆ2.3 Hz),
7.09 (1H, t, Jˆ7.7 Hz), 7.17 (1H, t, Jˆ7.7 Hz), 7.31 (1H, d,
Jˆ7.7 Hz), 7.67 (1H, d, Jˆ7.7 Hz), 8.42 (1H, brs); 13C
NMR (CDCl3) d 20.7, 21.6, 27.8, 30.7, 47.2, 56.8, 81.0,
110.9, 114.1, 119.0, 119.7, 121.7, 121.9, 128.6, 135.8,
174.8; MS (EI) m/z 302 (M1), 201, 172, 158, 130; HRMS
calcd for C18H26N2O2 302.1994. Found: 302.1988. Anal.
Calcd for C18H26N2O2: C, 71.49; H, 8.67; N, 9.26. Found:
C, 71.71; H, 8.83; N, 9.46.
General procedure for the preparation of amino esters
6a±f by the debenzylation of carbamate esters 5a±f
A solution of carbamate esters 5a±f (2.45±7.80 g, 6.00±
16.8 mmol) in a mixture of ethanol (70±120 mL), acetic
acid (0.570±1.21 g, 0.54±1.15 mL, 9.50±20.2 mmol), and,
when necessary, ethyl acetate (70 mL) as co-solvent was
hydrogenated over 10% Pd/C (0.368±1.95 g). After hydro-
gen consumption had ceased, the catalyst was ®ltered off
over celite, and the solvent was evaporated under reduced
pressure. The residue was dissolved in CH2Cl2, the pH was
rendered alkaline (pHˆ9) by 10% Na2CO3 solution, and the
organic phase was either puri®ed by Chromatotronw or
directly crystallized to give aminoesters 6a±f.
(2Sp,3Rp)- and (2Sp,3Sp)-b-(3-Pentyl)-tryptophan tert-
butyl ester (6c). From 5c: 7.80 g (16.8 mmol), EtOH:

C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
5487
120 mL, AcOH: 1.15 mL, Pd/C catalyst: 1.95 g. Yield:
3.90 g (70%). The two diastereomers were separated by
Chromatotronw (CH2Cl2). The analytical samples were
crystallized from ether.
119.2, 121.8, 122.4, 126.7, 126.8, 128.3, 128.8, 136.1,
140.6, 173.6; MS (EI) m/z 336 (M1), 278, 235, 207;
HRMS calcd for C21H24N2O2 336.1838. Found: 336.1836.
Anal. Calcd for C21H24N2O2´0.5H2O: C, 73.02; H, 7.30; N,
8.11. Found: C, 73.14; H, 7.05; N, 8.20.
(2Sp,3Rp)-6c: mp 159±1608C; IR (KBr) 3370, 2965,
1
1722 cm21; H NMR (CDCl3) d 0.86 (3H, t, Jˆ6.8 Hz),
(2Sp,3Sp)-6e: mp 150±1528C; IR (KBr) 3410, 3059,
1
1.00 (3H, t, Jˆ6.8 Hz), 1.12 (9H, s), 1.22±1.68 (6H, m),
1.93 (1H, m), 3.31 (1H, t, Jˆ7.7 Hz), 3.75 (1H, d,
Jˆ7.7 Hz), 6.99 (1H, d, Jˆ1.8 Hz), 7.05±7.20 (2H, m),
7.32 (1H, d, Jˆ7.7 Hz), 7.64 (1H, d, Jˆ7.7 Hz), 8.09 (1H,
brs); 13C NMR (CDCl3) d 11.5, 11.6, 22.7, 23.0, 27.5, 41.7,
42.7, 58.2, 80.4, 110.8, 114.1, 119.1, 119.5, 121.5, 122.5,
128.9, 135.5, 174.9; MS (EI) m/z 330 (M1), 200, 130. Anal.
Calcd for C20H30N2O2: C, 72.69; H, 9.15; N, 8.47. Found: C,
72.49; H, 8.92; N, 8.30.
1724 cm21; H NMR (CDCl3) d 1.18 (9H, s), 1.67 (2H,
brs), 4.14 (1H, d, Jˆ8.6 Hz), 4.59 (1H, d, Jˆ8.6 Hz), 7.04
(1H, t, Jˆ8.3 Hz), 7.11±7.42 (7H, m), 7.51 (1H, d,
Jˆ8.3 Hz), 8.21 (1H, brs); 13C NMR (CDCl3) d 27.3,
48.5, 59.6, 81.2, 111.2, 114.3, 118.6, 119.0, 121.6, 121.8,
126.3, 127.1, 128.0, 128.3, 136.2, 141.4, 173.1; MS m/z 336
(M1), 261, 235, 206; HRMS calcd for C21H24N2O2
336.1838. Found: 336.1836. Anal. Calcd for
C21H24N2O2´0.5H2O: C, 73.02; H, 7.30; N, 8.11. Found:
C, 72.70; H, 7.01; N, 7.87.
(2Sp,3Sp)-6c: mp 111±1138C; IR (KBr) 3377, 3171, 2967,
1
1722 cm21; H NMR (CDCl3) d 0.77 (3H, t, Jˆ6.8 Hz),
(2Sp,3Rp)- and (2Sp,3Sp)-b-(2,5-Dimethoxyphenyl)-tryp-
tophan tert-butyl ester (6f). From 5f: 3.18 g (6.00 mmol),
EtOH: 70 mL, AcOH: 0.54 mL, EtOAc: 70 mL, Pd/C cata-
lyst: 0.477 g. Yield: 2.02 g (85%). The two diastereomers
were separated by Chromatotronw (CH2Cl2/MeOH/concd
NH4OH, 98.5:1:0.5). The analytical sample of (2Sp,3Rp)-6f
was crystallized from ether.
0.98 (3H, t, Jˆ6.8 Hz), 1.28 (9H, s), 1.30±1.58 (6H, m),
1.82 (1H, m), 3.43 (1H, dd, Jˆ5.0, 9.0 Hz), 3.85 (1H, d,
Jˆ5.0 Hz), 6.99 (1H, d, Jˆ1.8 Hz), 7.06±7.19 (2H, m), 7.30
(1H, d, Jˆ7.7 Hz), 7.67 (1H, d, Jˆ7.7 Hz), 8.39 (1H, brs);
13C NMR (CDCl3) d 9.9, 11.2, 21.9, 22.4, 27.6, 42.1, 42.2,
56.6, 80.9, 111.0, 114.0, 119.0, 119.7, 121.7, 122.1, 128.7,
135.8, 174.9; MS (EI) m/z 330 (M1), 200, 130; HRMS calcd
for C20H30N2O2 330.2312. Found: 330.2307. Anal. Calcd for
C20H30N2O2: C, 72.69; H, 9.15; N, 8.47. Found: C, 72.72; H,
9.23; N, 8.57.
(2Sp,3Rp)-6f: mp 104±1058C; IR (KBr) 3401, 3375, 2978,
1724 cm21; 1H NMR (CDCl3) d 1.15 (9H, s), 1.71 (2H, brs),
3.66 (3H, s), 3.82 (3H, s), 4.26 (1H, d, Jˆ7.4 Hz), 5.04 (1H,
d, Jˆ7.4 Hz), 6.67 (1H, dd, Jˆ2.8, 7.9 Hz), 6.77 (1H, d,
Jˆ7.9 Hz), 6.91 (1H, d, Jˆ2.1 Hz), 7.03 (1H, t, Jˆ
7.8 Hz), 7.12 (1H, t, Jˆ7.8 Hz), 7.24 (1H, d, Jˆ2.8 Hz),
7.26 (1H, d, Jˆ7.8 Hz), 7.59 (1H, d, Jˆ7.8 Hz), 8.67 (1H,
brs); 13C NMR (CDCl3) d 27.5, 41.1, 55.5, 56.0, 58.2, 80.7,
111.0, 111.3, 111.4, 114.9, 116.8, 118.9, 119.1, 121.7,
122.4, 127.8, 131.3, 135.8, 151.2, 153.3, 173.6; MS (EI)
m/z 396 (M1), 365, 341, 295, 266, 130. Anal. Calcd for
C23H28N2O4: C, 69.68; H, 7.12; N, 7.06. Found: C, 70.01;
H, 7.35; N, 7.10.
(2Sp,3Rp)- and (2Sp,3Sp)-b-Cyclohexyltryptophan tert-
butyl ester (6d). From 5d: 6.81 g (14.3 mmol), EtOH:
105 mL, AcOH: 0.98 mL, Pd/C catalyst: 1.75 g, crystalliza-
tion: ether. Yield: 3.20 g (65%); mp 220±2228C (dec); IR
1
(KBr) 3362, 3190, 2977, 1722 cm21; H NMR (CDCl3) d
0.70±1.40 (5H, m), 1.18 (1.26) (9H, s), 1.49±1.94 (7H, m),
(2.00) 2.03 (1H, m), 3.12 (3.18) [1H, t, Jˆ8.2 Hz (dd,
Jˆ5.0, 8.7 Hz)], 3.77 (3.90) [1H, d, Jˆ8.2 (5.0) Hz], 6.97
(1H, d, Jˆ1.9 Hz), 7.03±7.21 (2H, m), 7.33 (1H, d,
Jˆ7.8 Hz), 7.63 (1H, d, Jˆ7.9 Hz), 8.12 (8.32) (1H, brs);
13C NMR (CDCl3) d 26.3 (26.4), 27.5 (27.8), 29.7 (30.8),
(31.8) 32.0, 38.9 (40.2), (46.1) 46.5, (55.9) 56.9, 80.7 (81.0),
110.9 (111.0), 113.5 (114.2), 118.8 (119.0), 119.1 (119.7),
121.3 (121.7), (121.9) 122.3, 128.7 (128.7), 135.6 (135.7),
174.5 (174.9) (Signals in brackets belong to the same dia-
stereomer); MS (EI) m/z 342 (M1), 241, 212, 158, 130.
Anal. Calcd for C21H30N2O2: C, 73.65; H, 8.83; N, 8.18.
Found: C, 73.34; H, 9.11; N, 8.16.
(2Sp,3Sp)-6f: viscous oil; IR (®lm) 3377, 2976, 1725 cm21
;
1H NMR (CDCl3) d 1.13 (9H, s), 1.77 (2H, brs), 3.65 (3H,
s), 3.79 (3H, s), 4.14 (1H, d, Jˆ8.6 Hz), 5.06 (1H, d,
Jˆ8.6 Hz), 6.67 (1H, dd, Jˆ2.4, 8.1 Hz), 6.78 (1H, d,
Jˆ8.1 Hz), 6.96 (1H, d, Jˆ2.1 Hz), 7.02 (1H, t, Jˆ
7.9 Hz), 7.10 (1H, t, Jˆ7.9 Hz), 7.17 (1H, d, Jˆ2.4 Hz),
7.25 (1H, d, Jˆ7.9 Hz), 7.58 (1H, d, Jˆ7.9 Hz), 8.53 (1H,
brs); 13C NMR (CDCl3) d 27.5, 39.9, 55.4, 56.0, 59.3, 80.6,
110.9, 111.3, 111.5, 115.6, 115.7, 119.0, 119.1, 121.7,
122.4, 127.2, 131.1, 135.8, 151.8, 153.4, 173.9; MS (EI)
m/z 396 (M1), 365, 341, 295, 266, 130. Anal. Calcd for
C23H28N2O4: C, 69.68; H, 7.12; N, 7.06. Found: C, 69.82;
H, 7.01; N, 7.10.
(2Sp,3Rp)- and (2Sp,3Sp)-b-Phenyltryptophan tert-butyl
ester (6e). From 5e: 2.82 g (6.00 mmol), EtOH: 70 mL,
AcOH: 0.54 mL, EtOAc: 70 mL, Pd/C catalyst: 0.423 g.
Yield: 1.49 g (74%). The two diastereomers were separated
by Chromatotronw (CH2Cl2/MeOH/concd NH4OH,
98.5:1:0.5). The analytical samples were crystallized from
ether.
General procedure for the preparation of tryptophans
7a±e,g from carbamate esters 5a,b,d,g and amino esters
6c,e
(2Sp,3Rp)-6e: mp 175±1768C; IR (KBr) 3410, 3057,
1
1726 cm21; H NMR (CDCl3) d 1.23 (9H, s), 1.56 (2H,
The appropriate carbamate ester 5 or amino ester 6 (150±
330 mg, 0.31±0.89 mmol) was dissolved in CH2Cl2 (5 mL),
cooled to 2108C, and 1 M BBr3 in CH2Cl2 (1.55±4.45 mL,
1.55±4.45 mmol, 5.0 equiv.) was added dropwise with stir-
ring. The stirring was continued at 2108C for 1 h and at
brs), 4.17 (1H, d, Jˆ7.2 Hz), 4.60 (1H, d, Jˆ7.2 Hz), 7.04
(1H, t, Jˆ7.8 Hz), 7.11 (1H, t, Jˆ7.8 Hz), 7.23±7.40 (7H,
m), 7.46 (1H, d, Jˆ7.8 Hz), 8.52 (1H, brs); 13C NMR
(CDCl3) d 27.6, 47.3, 59.4, 81.1, 111.0, 116.1, 119.1,

5488
C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
room temperature for 5 h. The excess of BBr3 was destroyed
by the careful addition of water (10±25 mL). The layers
were separated, the organic phase was washed with water,
and the combined aqueous layers were evaporated to
dryness. MeOH was evaporated several times from the resi-
due. Crude tryptophans 7a±e,g were puri®ed on preparative
TLC plates (BuOH/MeOH/concd NH4OH, 5:4:1) and then
solidi®ed with hexane/ether.
(2Sp,3Rp)- and (2Sp,3Sp)-b-(3-Pentyl)-tryptophan (7c).
From 6c: 200 mg (0.61 mmol), 1 M BBr3 in CH2Cl2:
3.05 mL (5.0 equiv.).
(2Sp,3Rp)-7c: yield 169 mg (78%); amorphous powder; IR
(KBr) 3455, 2928, 1707 cm21; 1H NMR (DMSO-d6) d 0.93
(3H, t, Jˆ7.2 Hz), 0.99 (3H, t, Jˆ7.3 Hz), 1.05±1.66 (4H,
m), 1.95 (1H, m), 3.69 (1H, brs), 4.13 (1H, d, Jˆ2.3 Hz),
7.20 (1H, t, Jˆ7.5 Hz), 7.29 (1H, d, Jˆ2.0 Hz), 7.43 (1H, t,
Jˆ7.5 Hz), 7.54 (1H, d, Jˆ7.5 Hz), 7.74 (1H, d, Jˆ7.5 Hz),
8.69 (3H, brs), 12.09 (1H, brs); 13C NMR (DMSO-d6) d
12.6, 12.8, 24.0, 24.4, 42.7, 43.2, 60.6, 111.7, 114.3,
121.1, 122.5, 122.6, 127.9, 136.5, 144.7, 170.4; MS (ESI)
m/z 275 (M111 for the free amino acid). Anal. Calcd for
C16H22N2O2´HBr´H2O: C, 51.48; H, 6.75; N, 7.50. Found: C,
51.20; H, 6.59; N, 7.58.
(2Sp,3Rp)- and (2Sp,3Sp)-b-Methyltryptophan (7a). From
5a: 300 mg (0.74 mmol), 1 M BBr3 in CH2Cl2: 3.70 mL
(5.0 equiv.).
(2Sp,3Rp)-7a: yield: 188 mg (85%); amorphous powder; IR
(KBr) 3420, 2905, 1736 cm21; 1H NMR (DMSO-d6) d 1.46
(3H, d, Jˆ7.2 Hz), 3.72 (1H, m), 4.10 (1H, brs), 6.90±7.14
(2H, m), 7.27 (1H, d, Jˆ2.0 Hz), 7.40 (1H, d, Jˆ8.0 Hz),
7.64 (1H, d, Jˆ8.0 Hz), 8.29 (3H, brs), 11.13 (1H, brs); 13C
NMR (DMSO-d6) d 17.2, 31.9, 57.0, 111.7, 113.0, 118.7,
118.8, 121.3, 123.9, 126.3, 136.4, 170.2; MS (ESI) m/z 219
(M111 for the free amino acid). Anal. Calcd for
C12H14N2O.2HBr´0.5H2O: C, 46.77; H, 5.23; N, 9.09.
Found: C, 47.11; H, 5.44; N, 9.32.
(2Sp,3Sp)-7c: yield: 195 mg (90%); amorphous powder; IR
(KBr) 3432, 2930, 1703 cm21; 1H NMR (DMSO-d6) d 0.91
(3H, t, Jˆ7.1 Hz), 0.99 (3H, t, Jˆ7.3 Hz), 1.07±1.70 (4H,
m), 2.22 (1H, m), 3.45 (1H, dd, Jˆ4.8, 9.8 Hz), 4.19 (1H, d,
Jˆ4.8 Hz), 6.98 (1H, t, Jˆ7.8 Hz), 7.07 (1H, t, Jˆ7.8 Hz),
7.15 (1H, d, Jˆ2.0 Hz), 7.38 (1H, d, Jˆ7.8 Hz), 7.57 (1H, d,
Jˆ7.8 Hz), 8.16 (3H, brs), 11.16 (1H, brs); 13C NMR
(DMSO-d6) d 9.6, 10.4, 21.2, 21.8, 40.8, 40.9, 54.3,
111.6, 114.3, 118.8, 121.2, 127.9, 128.0, 136.6, 144.7,
171.1; MS (ESI) m/z 275 (M111 for the free amino acid).
Anal. Calcd for C16H22N2O2´HBr´H2O: C, 51.48; H, 6.75; N,
7.50. Found: C, 51.85; H, 7.09; N, 7.61.
(2Sp,3Sp)-7a: yield: 202 mg (91%); amorphous powder; IR
(KBr) 3418, 2914, 1736 cm21; 1H NMR (DMSO-d6) d 1.44
(3H, d, Jˆ7.1 Hz), 3.39 (1H, m), 4.12 (1H, brs), 7.02 (1H, t,
Jˆ7.5 Hz), 7.11 (1H, t, Jˆ7.5 Hz), 7.25 (1H, d, Jˆ3.0 Hz),
7.41 (1H, d, Jˆ7.5 Hz), 7.58 (1H, d, Jˆ7.5 Hz), 8.17 (3H,
brs), 11.16 (1H, brs); 13C NMR (DMSO-d6) d 16.0, 31.9,
57.0, 111.9, 112.8, 118.4, 118.8, 121.4, 124.0, 126.1, 136.6,
170.5; MS (ESI) m/z 219 (M111 for the free amino acid).
Anal. Calcd for C12H14N2O2´HBr´H2O: C, 45.44; H, 5.40; N,
8.83. Found: C, 45.70; H, 5.69; N, 8.80.
(2Sp,3Rp)- and (2Sp,3Sp)-b-Cyclohexyltryptophan (7d).
From 5d: 300 mg (0.63 mmol), 1 M BBr3 in CH2Cl2:
3.15 mL (5.0 equiv.). Yield: 188 mg (81%); amorphous
1
powder; IR (KBr) 3472, 3422, 2924, 1728 cm21; H NMR
(DMSO-d6) d 0.65±1.80 (10H, m), 1.90 (2.10) (1H, m),
(3.30) 3.43 (1H, brs), 4.25 (1H, m), 6.90±7.85 (5H, m),
(8.21) 8.67 (3H, brs), (11.15) 12.07 (1H, brs); 13C NMR
(DMSO-d6) d 25.7 (25.9), 26.2 (26.3), 29.8 (30.4), (37.8)
38.6, 44.3 (44.3), (53.8) 54.2, 109.2 (109.3), 111.6 (111.7),
114.3 (119.1), 118.6 (118.7), (121.1) 121.2, 124.1 (124.9),
136.0 (136.2), 144.7 (144.9), (170.6) 171.1 (Signals in
brackets belong to the same diastereomer); MS (ESI) m/z
287 (M111 for the free amino acid). Anal. Calcd for
C17H22N2O2´HBr´0.5H2O: C, 54.26; H, 6.43; N, 7.44.
Found: C, 54.55; H, 6.12; N, 7.81.
(2Sp,3Rp)- and (2Sp,3Sp)-b-Isopropyltryptophan (7b).
From 5b: 330 mg (0.76 mmol), 1 M BBr3 in CH2Cl2:
3.80 mL (5.0 equiv.).
(2Sp,3Rp)-7b: yield 217 mg (87%); amorphous powder; IR
1
(KBr) 3405, 3352, 2963, 1728 cm21; H NMR (DMSO-d6)
d 0.70 (3H, d, Jˆ5.9 Hz), 1.11 (3H, d, Jˆ5.9 Hz), 2.49 (1H,
m), 3.28 (1H, dd, Jˆ5.0, 8.1 Hz), 4.19 (1H, d, Jˆ5.0 Hz),
6.98 (1H, t, Jˆ7.7 Hz), 7.09 (1H, t, Jˆ7.7 Hz), 7.19 (1H,
brs), 7.38 (1H, d, Jˆ7.7 Hz), 7.58 (1H, d, Jˆ7.7 Hz), 8.36
(3H, brs), 11.20 (1H, brs); 13C NMR (DMSO-d6) d 20.8,
21.7, 32.1, 45.4, 54.2, 109.5, 111.6, 118.6, 119.2, 121.0,
124.9, 127.7, 136.3, 170.5; MS (ESI) m/z 247 (M111 for
the free amino acid). Anal. Calcd for C14H18N2O2´HBr´H2O:
C, 48.71; H, 6.13; N, 8.11. Found: C, 48.53; H, 6.00; N, 8.02.
(2Sp,3Rp)- and (2Sp,3Sp)-b-Phenyltryptophan (7e). From
6e: 300 mg (0.89 mmol), 1 M BBr3 in CH2Cl2: 4.45 mL
(5.0 equiv.).
(2Sp,3Rp)-7e: yield: 296 mg (92%); amorphous powder; IR
(KBr) 3418, 2888, 1738 cm21; 1H NMR (DMSO-d6) d 4.71
(1H, m), 4.78 (1H, d, Jˆ9.0 Hz), 6.95 (1H, t, Jˆ7.4 Hz),
7.06 (1H, t, Jˆ7.4 Hz), 7.18±7.48 (7H, m), 7.53 (1H, d,
Jˆ7.4 Hz), 8.42 (3H, brs), 11.20 (1H, brs); 13C NMR
(DMSO-d6) d 43.9, 56.4, 111.7, 112.0, 118.4, 118.8,
121.4, 123.8, 126.5, 127.3, 128.8, 128.9, 136.0, 139.6,
170.3; MS (ESI) m/z 281 (M111 for the free amino acid).
Anal. Calcd for C17H16N2O2´HBr´H2O: C, 53.84; H, 5.05; N,
7.38. Found: C, 53.46; H, 4.71; N, 7.21.
(2Sp,3Sp)-7b: yield 162 mg (65%); amorphous powder; IR
1
(KBr) 3362, 3258, 2965, 1750 cm21; H NMR (DMSO-d6)
d 0.82 (3H, d, Jˆ6.2 Hz), 1.02 (3H, d, Jˆ6.2 Hz), 2.28 (1H,
m), 3.39 (1H, dd, Jˆ5.0, 8.6 Hz), 4.24 (1H, d, Jˆ5.0 Hz),
7.01 (1H, t, Jˆ7.8 Hz), 7.10 (1H, t, Jˆ7.8 Hz), 7.29 (1H, d,
Jˆ3.6 Hz), 7.40 (1H, d, Jˆ7.8 Hz), 7.55 (1H, d, Jˆ7.8 Hz),
8.20 (3H, brs), 11.08 (1H, brs); 13C NMR (DMSO-d6) d
20.3, 21.6, 29.3, 43.9, 54.6, 109.0, 111.5, 118.7, 118.8,
121.2, 124.2, 128.1, 136.1, 171.0; MS (ESI) m/z 247
(M111 for the free amino acid). Anal. Calcd for
C14H18N2O2´HBr´H2O: C, 48.71; H, 6.13; N, 8.11. Found:
C, 48.36; H, 6.40; N, 8.29.
(2Sp,3Sp)-7e: yield: 266 mg (83%); amorphous powder; IR
1
(KBr) 3252, 2882, 2778, 1676 cm21; H NMR (DMSO-d6)

C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
5489
d 4.65 (1H, d, Jˆ8.3 Hz), 4.73 (1H, m), 6.98 (1H, t,
Jˆ7.6 Hz), 7.07 (1H, t, Jˆ7.6 Hz), 7.11±7.53 (7H, m),
7.77 (1H, d, Jˆ1.5 Hz), 8.45 (3H, brs), 11.30 (1H, brs);
13C NMR (DMSO-d6) d 44.6, 56.4, 111.7, 112.2, 118.4,
118.8, 121.5, 123.5, 126.7, 127.2, 128.5, 128.7, 136.4,
140.0, 170.2; MS (ESI) m/z 281 (M111 for the free
amino acid). Anal. Calcd for C17H16N2O2´HBr´0.5H2O: C,
55.15; H, 4.90; N, 7.56. Found: C, 55.50; H, 4.66; N, 7.42.
d, Jˆ2.8 Hz), 7.06 (1H, t, Jˆ7.8 Hz), 7.37 (1H, d,
Jˆ7.8 Hz), 7.48 (1H, d, Jˆ3.2 Hz), 7.90±7.98 (3H, m),
8.30 (3H, brs), 11.14 (1H, brs); 13C NMR (DMSO-d6) d
37.8, 55.4, 55.9, 56.2, 111.6, 112.1, 112.2, 112.3, 116.9,
118.5, 118.6, 121.2, 124.1, 127.0, 129.1, 136.1, 150.4,
153.2, 170.9; MS (ESI) m/z 341 (M111 for the free
amino acid). Anal. Calcd for C19H20N2O4´CF3-
COOH´1.5H2O: C, 52.39; H, 5.03; N, 5.82. Found: C,
52.65; H, 5.40; N, 6.11.
(2Sp,3Rp)- and (2Sp,3Sp)-b-Methyl-5-bromotryptophan
(7g). From 5g: 150 mg (0.31 mmol), 1 M BBr3 in CH2Cl2:
1.55 mL (5.0 equiv.).
General procedure for the Pictet±Spengler cyclization of
amino esters 6a±c,e,f into tetrahydro-b-carbolines
8a±c,e,f
(2Sp,3Rp)-7g: yield: 96 mg (82%); amorphous powder; IR
(KBr) 3383, 2928, 1732 cm21; 1H NMR (DMSO-d6) d 1.43
(3H, d, Jˆ7.2 Hz), 3.67 (1H, m), 4.08 (1H, d, Jˆ4.9 Hz),
7.19 (1H, dd, Jˆ1.9, 8.6 Hz), 7.34 (1H, d, Jˆ3.6 Hz), 7.37
(1H, d, Jˆ8.6 Hz), 7.96 (1H, d, Jˆ1.9 Hz), 8.31 (3H, brs),
11.37 (1H, brs); 13C NMR (DMSO-d6) d 16.9, 31.0, 57.1,
111.5, 113.1, 113.8, 121.0, 123.8, 125.6, 128.2, 135.1,
170.2; MS (ESI) m/z 289/287 (M111 for the free amino
acid). Anal. Calcd for C12H13BrN2O2´HBr´H2O: C, 36.39; H,
4.07; N, 7.07. Found: C, 36.76; H, 4.29; N, 6.94.
The mixture of the particular amino ester 6 (110±158 mg,
0.40 mmol), cyclohexanone (1.60±3.50 mmol, 4.0±7.0
equiv.), and, when necessary, a catalytic amount of acetic
acid (0.05±0.1 equiv.) was heated at 1208C in dry toluene
under nitrogen atmosphere in a Dean-Stark apparatus for
1.5±24 h. The heating was continued until the full consump-
tion of the starting material 6 (TLC monitoring). The
solvent was evaporated under reduced pressure, and the
residue was submitted to column chromatography
(CH2Cl2) to give tetrahydro-b-carbolines 8.
(2Sp,3Sp)-7g: yield: 89 mg (76%); amorphous powder; IR
(KBr) 3412, 2969, 1740 cm21 1H NMR (DMSO-d6) d
;
1.43 (3H, d, Jˆ7.2 Hz), 3.70 (1H, m), 4.12 (1H, brs), 7.21
(1H, dd, Jˆ1.7, 8.6 Hz), 7.29 (1H, d, Jˆ2.5 Hz), 7.39 (1H,
d, Jˆ8.6 Hz), 7.76 (1H, d, Jˆ1.7 Hz), 8.20 (3H, brs), 11.39
(1H, brs); 13C NMR (DMSO-d6) d 16.4, 31.7, 57.1, 111.5,
112.7, 113.9, 120.8, 123.9, 125.7, 128.1 135.3, 170.4; MS
(ESI) m/z 289/287 (M111 for the free amino acid). Anal.
Calcd for C12H13BrN2O2´HBr´H2O: C, 36.39; H, 4.07; N,
7.07. Found: C, 36.27; H, 3.88; N, 7.17.
cis-(3Sp,4Rp)- and trans-(3Sp,4Sp)-4-Methyl-1,2,3,4-tetra-
hydrospiro[b-carboline-1,10-cyclohexane]-3-carboxylic
acid tert-butyl ester (8a). From 6a: 110 mg (0.40 mmol),
cyclohexanone: 157 mg (1.6 mmol), re¯ux: 3.5 h [for cis-
(3Sp,4Rp)-8a] or 24 h [for trans-(3Sp,4Sp)-8a].
cis-(3Sp,4Rp)-8a: yield: 128 mg (90%); oil; IR (®lm) 3379,
;
2965, 1715 cm21 1H NMR (CDCl3) d 1.20 (3H, d,
Jˆ6.8 Hz), 1.39±1.96 (10H, m), 1.58 (9H, s), 2.00 (1H,
brs), 3.35 (1H, m), 3.85 (1H, d, Jˆ4.0 Hz), 7.02±7.18
(2H, m), 7.29 (1H, d, Jˆ7.7 Hz), 7.52 (1H, d, Jˆ7.7 Hz),
7.99 (1H, s); 13C NMR (CDCl3) d 15.6, 21.2, 21.4, 25.5,
28.2, 29.9, 34.3, 38.9, 52.3, 56.3, 81.0, 110.6, 113.2, 117.6,
119.1, 121.2, 126.4, 135.7, 140.3, 172.4; MS (EI) m/z 354
(M1), 255; HRMS calcd for C22H30N2O2 354.2307. Found:
354.2322. Anal. Calcd for C22H30N2O2: C, 74.54; H, 8.53;
N, 7.90. Found: C, 74.67; H, 8.77; N, 7.96.
Cleavage of amino ester 6f by tri¯uoroacetic acid
(2Sp,3Rp)- and (2Sp,3Sp)-b-(2,5-dimethoxy)-phenyltryp-
tophan (7f). A solution of 300 mg (0.76 mmol) of 6f in a
mixture of TFA (9.5 mL) and water (0.5 mL) was stirred in
the presence of Cleland's reagent (6 mg) at room
temperature for 3 h. After evaporation of the solvent, the
residue was crystallized from ether to give 7f as tri¯uoro-
acetate salt.
trans-(3Sp,4Sp)-8a: yield: 89 mg (63%); oil; IR (®lm) 3415,
1
3369, 2976, 1726 cm21; H NMR (CDCl3) d 1.48 (3H, d,
(2Sp,3Rp)-7f: yield: 331 mg (96%); amorphous powder; IR
(KBr) 3410, 3229, 2953, 1728 cm21; 1H NMR (DMSO-d6)
d 3.65 (3H, s), 3.85 (3H, s), 4.74 (1H, d, Jˆ9.2 Hz), 5.20
(1H, d, Jˆ9.2 Hz), 6.74 (1H, dd, Jˆ2.9, 8.8 Hz), 6.86±6.95
(2H, m), 6.98 (1H, t, Jˆ8.0 Hz), 7.09 (1H, t, Jˆ8.0 Hz),
7.39 (1H, d, Jˆ8.0 Hz), 7.48 (1H, d, Jˆ8.0 Hz), 7.71 (1H,
brs), 8.39 (3H, brs), 11.25 (1H, brs); 13C NMR (DMSO-d6)
d 36.9, 55.4, 55.8, 56.4, 111.7, 112.3, 112.4, 112.5, 116.5,
118.5, 118.8, 121.5, 123.8, 127.1, 129.2, 136.3, 150.9,
153.2, 170.2; MS (ESI) m/z 341 (M111 for the free
amino acid). Anal. Calcd for C19H20N2O4´CF3-
COOH´1.5H2O: C, 52.39; H, 5.03; N, 5.82. Found: C,
52.08; H, 5.31; N, 6.20.
Jˆ6.8 Hz), 1.50±2.01 (11H, m), 1.56 (9H, s), 3.15 (1H, m),
3.30 (1H, d, Jˆ9.4 Hz), 7.02±7.18 (2H, m), 7.31 (1H, d,
Jˆ7.7 Hz), 7.61 (1H, d, Jˆ7.7 Hz), 7.85 (1H, s); 13C NMR
(CDCl3) d 18.3, 21.1, 21.3, 25.8, 28.2, 32.7, 35.5, 36.3, 51.8,
60.9, 81.1, 110.8, 111.1, 119.2, 119.6, 121.1, 126.9, 135.7,
141.0, 173.3; MS (EI) m/z 354 (M1), 255; HRMS calcd for
C22H30N2O2 354.2307. Found: 354.2301. Anal. Calcd for
C22H30N2O2: C, 74.54; H, 8.53; N, 7.90. Found: C, 74.19;
H, 8.65; N, 7.77.
cis-(3Sp,4Rp)- and trans-(3Sp,4Sp)-4-Isopropyl-1,2,3,4-
tetrahydrospiro[b-carboline-1,10-cyclohexane]-3-car-
boxylic acid tert-butyl ester (8b). From 6b: 121 mg
(0.40 mmol), cyclohexanone: 157 mg (1.6 mmol), AcOH:
3 mg (0.05 mmol), re¯ux: 1.5 h [for cis-(3Sp,4Rp)-8b] or
8 h [for trans-(3Sp,4Sp)-8b]. The analytical samples were
crystallized from ether.
(2Sp,3Sp)-7f: yield: 324 mg (94%); amorphous powder; IR
(KBr) 3406, 3239, 2957, 1674 cm21; 1H NMR (DMSO-d6)
d 3.63 (3H, s), 3.83 (3H, s), 4.54 (1H, d, Jˆ8.3 Hz), 5.11
(1H, d, Jˆ8.3 Hz), 6.76 (1H, dd, Jˆ3.2, 8.7 Hz), 6.87 (1H,

5490
C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
cis-(3Sp,4Rp)-8b: yield: 128 mg (90%); mp 225±2278C; IR
cis-(3Sp,4Rp)- and trans-(3Sp,4Sp)-4-Phenyl-1,2,3,4-tetra-
hydrospiro[b-carboline-1,10-cyclohexane]-3-carboxylic
acid tert-butyl ester (8e). From 6e: 134 mg (0.40 mmol),
cyclohexanone: 275 mg (2.8 mmol), AcOH: 3 mg
(0.05 mmol), re¯ux: 10 h [for cis-(3Sp,4Rp)-8e] or 7 h [for
trans-(3Sp,4Sp)-8e]. The analytical samples were crystal-
lized from methanol or ether.
1
(KBr) 3440, 2930, 1707 cm21; H NMR (CDCl3) d 0.79
(3H, d, Jˆ5.9 Hz), 1.22 (3H, d, Jˆ5.9 Hz), 1.57 (9H, s),
1.59±1.90 (10H, m), 1.99 (1H, m), 2.13 (1H, brs), 3.21
(1H, dd, Jˆ2.9, 3.5 Hz), 3.78 (1H, d, Jˆ3.5 Hz), 7.09
(1H, t, Jˆ7.7 Hz), 7.14 (1H, t, Jˆ7.7 Hz), 7.32 (1H, d,
Jˆ7.7 Hz), 7.56 (1H, d, Jˆ7.7 Hz), 7.79 (1H, s); 13C
NMR (CDCl3) d 21.1, 21.2, 21.6, 25.3, 25.4, 28.2, 30.2,
34.3, 38.2, 41.3, 52.6, 58.1, 81.0, 110.1, 110.6, 119.1,
119.5, 121.0, 128.1, 135.8, 141.3, 172.8; MS (EI) m/z 382
(M1), 283, 195, 182; HRMS calcd for C24H34N2O2
382.2620. Found: 382.2633. Anal. Calcd for C24H34N2O2:
C, 75.36; H, 8.96; N, 7.32. Found: C, 75.02; H, 9.15; N,
7.23.
cis-(3Sp,4Rp)-8e: yield: 150 mg (90%); mp 219.5±2218C
1
(dec) (methanol); IR (KBr) 3370, 2928, 1717 cm21; H
NMR (CDCl3) d 1.32 (9H, s), 1.48±2.07 (11H, m), 4.13
(1H, d, Jˆ4.5 Hz), 4.45 (1H, d, Jˆ4.5 Hz), 6.94 (1H, t,
Jˆ7.4 Hz), 7.07 (1H, t, Jˆ7.4 Hz), 7.12±7.28 (6H, m),
7.36 (1H, d, Jˆ7.4 Hz), 7.87 (1H, s); 13C NMR (CDCl3) d
21.3, 21.5, 25.6, 28.0, 34.3, 39.0, 41.7, 52.2, 57.2, 81.2,
110.6, 110.9, 118.4, 119.4, 121.5, 126.6, 126.7, 127.8,
129.4, 135.8, 140.8, 141.1, 171.1; MS (EI) m/z 416 (M1),
360, 315, 287; HRMS calcd for C27H32N2O2 416.2464.
Found: 416.2455. Anal. Calcd for C27H32N2O2: C, 77.85;
H, 7.74; N, 6.72. Found: C, 77.49; H, 7.61; N, 6.66.
trans-(3Sp,4Sp)-8b: yield: 99 mg (65%); 227±2298C; IR
1
(KBr) 3385, 2932, 1711 cm21; H NMR (CDCl3) d 0.84
(3H, d, Jˆ5.9 Hz), 1.07 (3H, d, Jˆ5.9 Hz), 1.43 (9H, s),
1.52±1.97 (11H, m), 2.45 (1H, m), 3.35 (1H, t,
Jˆ5.8 Hz), 3.68 (1H, d, Jˆ5.8 Hz), 7.00 (1H, t, Jˆ
7.7 Hz), 7.12 (1H, t, Jˆ7.7 Hz), 7.30 (1H, d, Jˆ7.7 Hz),
7.58 (1H, d, Jˆ7.7 Hz), 7.83 (1H, s); 13C NMR (CDCl3) d
18.7, 21.4, 21.4, 21.5, 25.8, 27.9, 30.8, 37.2, 38.0, 40.9,
51.6, 55.3, 80.6, 109.9, 110.6, 119.1, 119.6, 121.0, 127.6,
135.7, 141.3, 174.2; MS (EI) m/z 382 (M1), 283, 238, 195,
182; HRMS calcd for C24H34N2O2 382.2620. Found:
382.2625. Anal. Calcd for C24H34N2O2: C, 75.36; H, 8.96;
N, 7.32. Found: C, 75.65; H, 9.05; N, 7.08.
trans-(3Sp,4Sp)-8e: yield: 148 mg (89%); mp 209±2108C
;
(ether); IR (KBr) 3402, 2926, 1709 cm21 1H NMR
(CDCl3) d 1.28 (9H, s), 1.46±2.15 (11H, m), 3.64 (1H, d,
Jˆ9.8 Hz), 4.17 (1H, d, Jˆ9.8 Hz), 6.52 (1H, d, Jˆ8.0 Hz),
6.77 (1H, t, Jˆ8.0 Hz), 7.03 (1H, t, Jˆ8.0 Hz), 7.15±7.31
(6H, m), 7.90 (1H, s); 13C NMR (CDCl3) d 21.0, 21.3, 25.8,
27.9, 35.9, 38.5, 46.2, 52.1, 61.6, 81.0, 110.0, 110.5, 119.1,
119.8, 121.2, 126.6, 126.7, 128.2, 128.9, 135.6, 141.7,
141.8, 172.6; MS (EI) m/z 416 (M1), 360, 315, 287;
HRMS calcd for C27H32N2O2 416.2464. Found: 416.2468.
Anal. Calcd for C27H32N2O2: C, 77.85; H, 7.74; N, 6.72.
Found: C, 78.06; H, 8.05; N, 6.38.
cis-(3Sp,4Rp)- and trans-(3Sp,4Sp)-4-(3-Pentyl)-1,2,3,4-
tetrahydrospiro[b-carboline-1,10-cyclohexane]-3-car-
boxylic acid tert-butyl ester (8c). From 6c: 132 mg
(0.40 mmol), cyclohexanone: 157 mg (1.6 mmol), re¯ux:
5 h [for cis-(3Sp,4Rp)-8c] or 4.5 h [for trans-(3Sp,4Sp)-8c].
The analytical samples were crystallized from ether.
trans-(3Sp,4Rp)- and cis-(3Sp,4Sp)-4-(2,5-Dimethoxy-
phenyl)-1,2,3,4-tetrahydrospiro[b-carboline-1,10-cyclo-
hexane]-3-carboxylic acid tert-butyl ester (8f). From 6f:
158 mg (0.40 mmol), cyclohexanone: 275 mg (2.8 mmol),
re¯ux: 5 h [for trans-(3Sp,4Rp)-8f] or 7 h [for cis-(3Sp,4Sp)-
8f]. The analytical samples were crystallized from ether.
cis-(3Sp,4Rp)-8c: yield: 161 mg (98%); mp 166±1678C; IR
1
(KBr) 3379, 2959, 1709 cm21; H NMR (CDCl3) d 0.68
(3H, t, Jˆ6.8 Hz), 1.03 (3H, t, Jˆ6.8 Hz), 1.10±1.82
(15H, m), 1.48 (9H, s), 2.00 (1H, m), 3.34 (1H, dd, Jˆ3.6,
3.8 Hz), 3.72 (1H, d, Jˆ3.8 Hz), 6.94±7.07 (2H, m), 7.21
(1H, d, Jˆ7.7 Hz), 7.43 (1H, d, Jˆ7.7 Hz), 7.99 (1H, s); 13C
NMR (CDCl3) d 12.2, 12.4, 21.2, 21.6, 24.9, 25.4, 25.9,
28.1, 34.2, 37.0, 38.6, 43.7, 52.5, 58.1, 81.0, 110.5, 110.7,
119.0, 119.2, 120.9, 127.7, 135.8, 141.4, 172.7; MS (EI) m/z
410 (M1), 311, 281, 238, 195, 182; HRMS calcd for
C26H38N2O2 410.2935. Found: 410.2933. Anal. Calcd for
C26H38N2O2: C, 76.06; H, 9.33; N, 6.82. Found: C, 75.76;
H, 9.65; N, 6.83.
trans-(3Sp,4Rp)-8f: yield: 162 mg (85%); mp 208±2108C;
1
IR (KBr) 3433, 3339, 2928, 1707 cm21; H NMR (CDCl3)
d 1.38 (9H, s), 1.43±2.13 (11H, m), 3.62 (6H, brs), 3.87
(1H, d, Jˆ9.1 Hz), 4.58 (1H, d, Jˆ9.1 Hz), 6.55±6.87 (5H,
m), 7.00 (1H, t, Jˆ8.0 Hz), 7.22 (1H, d, Jˆ8.0 Hz), 7.90
(1H, s); 13C NMR (CDCl3) d 21.0, 21.3, 25.9, 27.8, 31.5,
35.8, 38.4, 52.0, 55.6, 58.1, 59.4, 80.6, 110.2, 110.4, 111.7,
111.9, 116.4, 119.0, 119.3, 120.9, 126.7, 131.7, 135.6,
141.0, 152.3, 153.7, 172.6; MS (EI) m/z 476 (M1), 420,
375, 347; HRMS calcd for C29H36N2O4 476.2675. Found:
476.2671. Anal. Calcd for C29H36N2O4: C, 73.08; H, 7.61;
N, 5.88. Found: C, 73.33; H, 7.42; N, 5.93.
trans-(3Sp,4Sp)-8c: yield: 117 mg (71%); mp 145±1468C;
1
IR (KBr) 3380, 2959, 1709 cm21; H NMR (CDCl3) d
0.70 (3H, t, Jˆ6.8 Hz), 0.98 (3H, t, Jˆ6.8 Hz), 1.03±1.85
(15H, m), 1.38 (9H, s), 1.90 (1H, m), 3.54 (1H, dd, Jˆ6.5,
6.6 Hz), 3.73 (1H, d, Jˆ6.6 Hz), 6.92±7.08 (2H, m), 7.21
(1H, d, Jˆ7.8 Hz), 7.51 (1H, d, Jˆ7.8 Hz), 7.86 (1H, s); 13C
NMR (CDCl3) d 12.5, 12.9, 21.4, 23.2, 24.0, 25.9, 27.0,
27.9, 36.9, 37.5, 37.6, 44.5, 51.5, 55.5, 80.6, 109.6, 110.6,
118.9, 119.6, 120.9, 127.3, 135.7, 141.6, 174.1; MS (EI) m/z
410 (M1), 309, 238, 195, 182; HRMS calcd for C26H38N2O2
410.2935. Found: 410.2940. Anal. Calcd for C26H38N2O2:
C, 76.06; H, 9.33; N, 6.82. Found: C, 75.96; H, 9.50; N,
7.01.
cis-(3Sp,4Sp)-8f: yield: 168 mg (88%); mp 142±1438C; IR
1
(KBr) 3433, 3339, 2928, 1732 cm21; H NMR (CDCl3) d
1.22 (9H, s), 1.40±2.01 (10H, m), 2.30 (1H, d, Jˆ6.8 Hz),
3.63 (3H, s), 3.91 (3H, s), 4.11 (1H, dd, Jˆ4.8, 6.8 Hz), 5.02
(1H, d, Jˆ4.8 Hz), 6.62 (1H, dd, Jˆ2.7, 8.2 Hz), 6.75 (1H,
d, Jˆ8.2 Hz), 6.94 (1H, t, Jˆ7.8 Hz), 7.05 (1H, t,
Jˆ7.8 Hz), 7.17 (1H, d, Jˆ7.8 Hz), 7.25 (1H, d, Jˆ
2.7 Hz), 7.34 (1H, d, Jˆ7.8 Hz), 8.00 (1H, s); 13C NMR
(CDCl3) d 21.1, 21.5, 25.5, 27.6, 32.2, 34.0, 38.7, 51.9,

C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
5491
11. Neef, G. G.; Eder, U.; Huth, A.; Rahtz, D. Heterocycles 1983,
20, 1295.
12. (a) Behforouz, M.; Zarrinmayeh, H.; Ogle, M. E.; Riehle, T. J.;
55.3, 55.6, 56.7, 80.6, 110.3, 110.5, 111.2, 111.5, 116.7,
118.6, 119.1, 121.3, 126.7, 131.5, 135.8, 140.8, 151.2,
153.0, 171.3; MS (EI) m/z 476 (M1), 420, 375, 347;
HRMS calcd for C29H36N2O4 476.2675. Found: 476.2673.
Anal. Calcd for C29H36N2O4: C, 73.08; H, 7.61; N, 5.88.
Found: C, 73.24; H, 7.32; N, 5.86.
È
Bell, F. W. J. Heterocycl. Chem. 1988, 25, 1627. (b) Spondlin, C.;
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13. (a) Boteju, L. W.; Wegner, K.; Qian, X.; Hruby, V. J.
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Acknowledgements
È
We thank Ph. Sigaut (MS, EI), P. Szabo (A. Szent-Gyorgyi
15. Gong, Y.; Kato, K.; Kimoto, H. Tetrahedron Lett. 1999, 40,
5743.
Medical University, Szeged, Hungary, MS, ESI), D. Royer
and C. Peterman (NMR) for spectroscopic measurements.
Financial support by ADIR and Co. (Laboratoires Servier) is
gratefully acknowledged.
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®guration of b-substituted tryptophans (7a,b,c,e,f) analytical

5492
C. Nemes et al. / Tetrahedron 56 (2000) 5479±5492
Â
È È
HPLC methods have already been developed: (a) Peter, A.; Torok,
Â
Vekes, E.; Sapi, J.; Laronze, M.; Laronze, J.-Y.; Armstrong,
D. W. Chromatographia 2000, 51, 165±174.
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other nomenclatures (e.g. erythro-threo) for the con®gurational
notation is not only confusing but in certain cases incorrect as well.
 Â
Wiley: New York, 1999; pp 300±301. (b) Peter, A.; Peter, M.;
Â
Â
È
È È
FuÈlop, F.; Torok, G.; Toth, G.; Tourwe, D.; Sapi, J.
Â
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Chromatographia 2000, 51, 148±154. (c) Torok, G.; Peter, A.;