Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK1 receptor antagonist

Article abstract of DOI:10.1021/jm010825z

This paper describes the synthesis and physical and biological effects of introducing different substituents at the α-position of the tryptophan containing neurokinin-1 receptor antagonist [(R)-2-(1H-indol-3-yl)-1-methyl-1-((S)-1 -phenyl-ethylcarbamoyl)-e

Full text of DOI:10.1021/jm010825z

2276
J . Med. Chem. 2001, 44, 2276-2285
Articles
Utiliza tion of a n In tr a m olecu la r Hyd r ogen Bon d To In cr ea se th e CNS
P en etr a tion of a n NK1 Recep tor An ta gon ist
Valerie A. Ashwood,† Mark J . Field,† David C. Horwell,† Christine J ulien-Larose,‡ Russell A. Lewthwaite,*,†
Scott McCleary,† Martyn C. Pritchard,† J enny Raphy,† and Lakhbir Singh†
Pfizer Global Research and Development, Cambridge University Forvie Site, Robinson Way, Cambridge CB2 2QB, U.K., and
Pfizer Global Research and Development, 3-9 Rue de la Loge, Fresnes Cedex 94265, France
Received J anuary 19, 2001
This paper describes the synthesis and physical and biological effects of introducing different
substituents at the R-position of the tryptophan containing neurokinin-1 receptor antagonist
[(R)-2-(1H-indol-3-yl)-1-methyl-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-
2-ylmethyl ester (CI 1021). The described compounds all exhibit less than 5 nM binding
affinities for the human neurokinin-1 receptor and selectivity over the tachykinin NK2 and
NK3 receptor subtypes. Application of variable temperature nuclear magnetic resonance
spectroscopy studies of the amide and urethane protons was utilized to determine the existence
of an intramolecular hydrogen bond. This intramolecular hydrogen bond increases the apparent
lipophilicity to allow increased central nervous system penetration and pharmacological activity
(gerbil foot tap test) in the case of the highest affinity compound [(S)-1-dimethylaminomethyl-
2-(1H-indol-3-yl)-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl
ester (P D 174424) over those analogues that could not form an intramolecular hydrogen bond.
In tr od u ction
is 0.6 in the rat) for a centrally acting compound. We
now report on the further development of compounds
from this class which retain nanomolar affinity binding
for the NK1 receptor and selectivity over the neuroki-
nin-2 and -3 receptors (NK2 and NK3), as well as
possessing increased aqueous solubility and a greater
potential to penetrate the CNS. We have previously
published on the structure-activity relationship (SAR)
studies on the N- and C-terminal substitutions of the
tryptophan moiety to give compound 1.7 The SAR of the
R-methyl group was then examined further. The des-
methyl analogue (12, P D 160226,8 Table 1) exhibited
good receptor binding affinity at the NK1 receptor (IC50
0.73 nM). To aid our understanding of the SAR of this
series of compounds, we sought to vary the nature of
the group at the R-position and probe this portion of the
molecule to determine its influence on the receptor
binding affinity of these compounds. We reasoned that
inclusion of appropriate heteroatoms at the R-carbon
atom could potentially lead to the formation of an
intramolecular hydrogen bond with one of the neighbor-
ing N-H’s from the urethane and amide groups. This
would effectively remove one donor hydrogen and one
acceptor atom from the molecule, which would then lead
to a higher apparent lipophilicity and, hence, may
increase membrane permeability9 while hopefully re-
taining increased aqueous solubility due to the presence
of the heteroatom. When the X-ray crystal structure of
1 (Figure 1) was examined, it was found that the
hydrogen atoms associated with the amide and urethane
groups were both pointing in the same general align-
ment with respect to each other and with the R-methyl
group of the tryptophan moiety.10 With the use of
Substance P has been shown to display preferential
affinity for the neurokinin-1 (NK1) tachykinin receptor,1
and it is widely acknowledged that this, and other
tachykinin agonists, play a major role in various biologi-
cal processes including pain transmission, vasodilation,
bronchoconstriction, activation of the immune system,
and neurogenic inflammation.2 Indeed, in recent years
the tachykinin area has been a focus of attention for
the pharmaceutical industry with many examples of
antagonists for each of the tachykinin receptors.3-6
We have previously reported on the design of the
selective NK1 receptor antagonist 1 (CI 1021, hNK1 IC50
) 1.05 nM).7 Although this compound has an excellent
pharmacological profile with oral bioavailability of 50-
60% (dog) and a half-life of greater than 6 h (dog), it
does exhibit poor aqueous solubility (<2 µg/mL) and a
modest brain-plasma ratio (brain homogenate to plasma
* Corresponding author: Russell A. Lewthwaite. Tel: +44 (0) 1223
210 929. Fax: +44 (0) 1223 249 106. E-mail: Russell.Lewthwaite@
Pfizer.com.
† Pfizer Global Research and DevelopmentsU.K.
‡ Pfizer Global Research and DevelopmentsFrance.
10.1021/jm010825z CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/09/2001

Effects of R-Substitution of an NK1 Receptor Antagonist
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14 2277
Sch em e 1a
Ta ble 1. Table Showing Some of the in Vitro Data for the
Compounds Described
compd
R
IC50 (nM)a
12
1
H
CH3
CH2CH3
CH2CH2CH3
CH2CH(CH3)2
CH2OCH3
CH2N(CH3)2
0.73 ( 0.19 (3)
1.05 ( 1.00 (51)
0.96 ( 0.25 (8)
0.85 ( 0.47 (3)
3.79 ( 2.18 (2)
0.70 ( 0.34 (11)
0.46 ( 0.17 (7)
11a
11b
11c
11d
11e
b
a
IC50 is the concentration producing half-maximal inhibition
of specific binding at the receptor and is an arithmetic mean given
with the standard deviation. The number of experiments are
indicated in brackets. ([125I]-Bolton Hunter-Substance P to NK1
b
receptors in IM9 cells.7) Mixture (3:2) of diastereomers at the
Trp center.
a
Reagents: (i) allyl alcohol, DCC, DMAP, CH2Cl2, 89%; (ii) TFA,
52%; (iii) ZCl, Na2CO3 (aq), 1,4-dioxane, 92%; (iv) LHMDS, RX,
DMPU, THF; (v) TFA, CH2Cl2 or H2SO4, MeOH, H2O.
development of an internal hydrogen bond by the
introduction of heteroatom containing substituents (e.g.,
methoxymethylene and dimethylaminomethylene). The
latter would also have the potential to increase the
aqueous solubility via intermolecular hydrogen bonds
to water.
There is literature precedent for the enantioselective
synthesis of R-methyltryptophan, and these methods
include chemical syntheses with varying degrees of
enantiopurity13-16 and enzymatic resolutions which give
excellent enantioselectivity.17,18 As a consequence of our
previous success with the method described by Crich
et al.19 in which the R-alkylation of Trp was achieved
with high enantioselectivity, it was decided to pursue
this approach in attempting to introduce R-substituents
incorporating heteroatoms stereoselectively. The general
synthesis of these types of compounds described by
Crich has been slightly modified.20 This modified syn-
thesis has been further modified due to low yields
obtained in the hydrolysis of the tryptophan methyl
ester when large groups were incorporated into the
R-positionspresumably as a consequence of unfavorable
steric interactions. Therefore, the allyl ester was chosen
as an acid protecting group as it is stable to the acidic
conditions required for both the ring-cyclization and
ring-opening, and it can be easily removed using cata-
lytic palladium in the presence of a nucleophile.21 The
synthesis started with the allyl esterification of (R)-N-
benzyloxycarboxytryptophan, 2, using N,N′-dicyclohexyl-
carbodiimide (DCC) as the condensing agent in excellent
yield (Scheme 1). It was found that partial racemization
of the R-center occurred when 4-(dimethylamino)pyri-
dine (DMAP) was used as catalyst. The absence of
F igu r e 1. Conformation of 1 obtained from X-ray crystal-
lography.
molecular modeling,11 a selection of compounds incor-
porating different R-substituents were proposed with the
aim of investigating intramolecular hydrogen bonding
and their effects on CNS penetration. The key synthetic
step to these compounds is an efficient and predictive
enantiomeric synthesis of R-substituted tryptophan
derivatives.
Ch em istr y
The R-methyl group of 1 serves as a conformational
constraint for the “backbone” of the molecule as well as
decreasing the potential for enzymatic hydrolysis and
racemization in vivo.12 It was hypothesized that the
R-substituent could be further adapted to give additional
conformational restriction of 1 via the introduction of a
bulkier alkyl group (ethyl, propyl, isobutyl) or the

2278 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14
Ashwood et al.
Sch em e 2a
a
Reagents: (i) Pd(PPh3)4, morpholine, THF; (ii) amine, HBTU, DIPEA, DMF; (iii) Pd(OH)2-C, EtOH; (iv) BfCH2OCOCl, TEA, EtOAc or
BfCH2OCONP, DMAP, DMF.
DMAP resulted in longer reaction times but no race-
mization. The cyclization reaction to give 4 was cata-
lyzed using trifluoroacetic acid (TFA),19 and the desired
tricycle was isolated as a single diastereomer in moder-
ate yield (52%). A second N-benzyloxycarboxy (Z) pro-
tecting group was introduced at the indoline nitrogen
using basic conditions in excellent yield. The enan-
tiospecific alkylations at the “R-carbon” proceeded in
good yield using lithium bis(trimethylsilyl)amide (LH-
MDS) as base in conjunction with the cosolvent 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)
at low temperature.20 Iodoethane had to be freshly
distilled from sodium in order to facilitate a clean
reaction in high yield to give 6a . Iodomethylmethyl
ether was chosen to give the ether, 6d , and the nitrogen
containing compound 6e was obtained using Eschen-
moser’s salt as the electrophile. These alkylated tricyclic
intermediates were then ring-opened using TFA in
dichloromethane. The N,N-dimethylaminomethyl com-
pound 6e was found to be quite stable to these condi-
tions, even the omission of solvent and conducting the
reaction in neat TFA did not provide any marked
improvement. Various acidic conditions were tried, and
the use of sulfuric acid in methanol was found to give
the optimal yield of ring-opened Trp ester, 7e. The ester
hydrolyses were facile when tetrakis(triphenylphos-
phine)palladium(0) was used in conjunction with a large
excess of morpholine,21 all giving near quantitative
yields of the free acids (Scheme 2). No attempt was
made at purification, and the acids were coupled to (S)-
1-phenylethylamine using 2-(1H-benzotriazol-1-yl)-1,1,3,3-
tetramethyluroniumhexafluorophosphate (HBTU) and
base in N,N-dimethylformamide (DMF). Compound 9e
gave only a moderate yield in the coupling reaction, and
this can probably be attributed to the enhanced steric
encumbrance of the large N,N-dimethylaminomethylene
group so close to the reaction center. The hydrogenolysis
of the two Z protecting groups proceeded in near
quantitative yield to give the free amine and indole
nitrogens. Initially these free amines were acylated with
4-nitrophenyl activated carbonates7 though it was sub-
sequently found that the corresponding chloroformates
gave cleaner and more rapid reactions in higher yields,
as exemplified by compound 11e, P D 174424, which
could not be obtained via the activated carbonate.
Resu lts a n d Discu ssion
It can be seen from Table 1 that the choice of
R-substituent has a minimal effect on the binding
affinity of the ligands to the NK1 receptor. The more
sterically demanding isobutyl group (11c, P D 307496,
3.46 nM), for example, has only 3- to 5-fold lower affinity
than the corresponding hydrogen (12, 0.73 nM) or
methyl substituted derivatives (1, 0.55 nM). The com-
pounds with a heteroatom in their R-substituent retain
the subnanomolar binding affinities for the NK1 recep-
tor. Most interestingly, the dimethylaminomethylene
group (11e, 0.46 nM) exhibited the highest affinity. A
comparison of the ethyl (11a , P D 170541, 0.96 nM) or
propyl (11b, P D 207746, 0.85 nM, 3:2 diastereomeric
mixture) substituents with the methoxymethyl (11d ,
P D 170540, 0.70 nM) substituent shows that the
presence of the heteroatom has no marked effect on the
binding of these ligands. However, comparing the steri-
cally similar isobutyl and dimethylaminomethylene
substituents, a noticeable difference in binding affinity
is observed, 11e retains (or even increases) affinity for
the NK1 receptor, while its all-carbon analogue, 11c, is
about 8 times less active.
Compounds 1 and 11e were compared to see if the
inclusion of an amine function has any beneficial effect
on aqueous solubility. Compound 1 exhibits low aqueous
solubility (2 µg/mL), and in a vehicle of PEG 400/
ethanol/water (40:15:45) it also exhibits low solubility
(0.76 mg/mL). Compound 11e, however, has the poten-
tial to form ammonium salts, and consequently its
hydrochloride exhibits superior solubility in both water

Effects of R-Substitution of an NK1 Receptor Antagonist
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14 2279
indicating that none of these hydrogen atoms are
involved in hydrogen bonding, either inter- or intramo-
lecularly. However, the amide proton of 11d (the meth-
oxymethylene compound) shows a large change in
chemical shift (0.9 ppm at 28 °C) from that of 1, and
11e (the N,N-dimethylaminomethylene compound) shows
an even greater shift (1.9 ppm at 28 °C). Both of these
amide protons also exhibit a temperature dependence,
as seen in Figure 2, where the chemical shift of the
amide proton moves downfield with decreasing temper-
ature (0.78 and 0.91 ppm for 11d and 11e, respectively)
for the temperature range 28 °C to -80 °C. From Table
2 it can be seen that both of these compounds have large
ppb/K values indicating that the amide proton is
involved in hydrogen bonding, the large ppb/K values
being indicative of the strengthening of the hydrogen
bond with decreasing temperature. This hydrogen bond
must be to the heteroatom in the R-substituent as the
amide hydrogen in the analogous carbon compound 11c
exhibits a very different resonance shift under the same
conditions. This suggests that the intramolecular hy-
drogen bond from the heteroatom to the amide hydro-
gen, making a six-membered ring, is favored over its
five-membered equivalent25 to the urethane proton, as
there is no evidence of temperature dependence for this
proton.
F igu r e 2. Temperature dependence of the urethane (dashed
line) and amide (continuous line) protons in CD2Cl2 (8 mg/0.7
mL).
Ta ble 2. Temperature Dependence of the Amide and Urethane
Protons in Deutero-dichloromethane
compd
amide H (ppb/K)a
urethane H (ppb/K)a
1
2.78
4.55b
7.22
8.43
-0.09
0.11b
11c
11d
11e
-2.95b
-0.65
a
Parts per billion per Kelvin, over the temperature range -80
b
°C to 28 °C. Parts per billion per Kelvin, over the temperature
range -60 °C to 28 °C.
An N,N-dimethylamino group was incorporated onto
the R-methyl group of the X-ray crystal structure of 1
and, using the modeling software, an intramolecular
hydrogen bond was formed separately to the urethane
and amide hydrogens. After minimizing the energy of
the system to allow the incorporation of the new moiety,
it was found that there was a bias toward the amidic
hydrogen bond in both energy (relative ∆E ) 3.1 K cal
mol-1) and bond lengths (2.1 and 2.4 Å for the urethane
and amide hydrogen bonds, respectively). Figure 3
shows the two structures and their respective hydrogen
bonds.
(0.5-0.7 mg/mL) and the PEG 400/ethanol/water vehicle
(10 mg/mL).
Recent literature has suggested that the chemical
shift of “acidic” protons, when examined by proton
nuclear magnetic resonance spectroscopy (NMR), show
temperature dependencies if hydrogen bonding occurs
in the system.22 This effect manifests itself as a change
in chemical shift of the hydrogen bonding proton, of the
hydrogen bond, as the bond is strengthened or weak-
ened by a variation in temperature. A lowering of the
temperature is more likely to develop the strength of
an inter-/ intra-molecular hydrogen bond due to the
raising of the energy barriers of rotation.23 The choice
of solvent also has a pivotal role. The use of a hydrogen
bonding solvent (e.g., deutero-dimethyl sulfoxide or
deutero-methanol) will encourage the formation of a
compound-solvent hydrogen bond rather than a com-
pound-compound interaction. Deuterodichloromethane
is the solvent of choice for low temperature NMR studies
due to its superior physical properties over other
solvents (e.g., deutero-chloroform, mp -64.1 °C24). A
study over a range of temperatures is desired as this
allows the calculation of the temperature dependence
of the chemical shift in parts per billion per Kelvin (ppb/
K). Studies with a tripeptide substrate have indicated
that a value in excess of about 5 ppb/K indicates the
presence of a geometrically optimal hydrogen bond.23
From Figure 2 and the results shown in Table 2, it
can be seen that there is a difference in the chemical
shifts for the compounds chosen for the low temperature
NMR studies. Using 1 as a “benchmark” (compound 12
was insoluble in deuterodichloromethane), it can be seen
that the amide proton (∼6.4 ppm) and the urethane
proton (∼5.4 ppm) are unaffected by the change in
temperature. Likewise, 11c, the isobutyl analogue,
shows little effect with the change in temperature from
28 °C to -60 °C. The urethane protons of 11d and 11e
are again largely unchanged by the drop in temperature,
Compound 1 has been shown to have a good phar-
macokinetic profile; however, for a centrally acting
compound its brain penetration is not remarkable, and
in fact the compound shows selectivity for the plasma
over the brain (brain homogenate-to-plasma ratio is
0.6).26 This modest ratio is, however, sufficient to exhibit
centrally mediated effects when dosed orally. In com-
parison, 11e has an increased preference for the brain
over plasma (brain homogenate-to-plasma ratio is 6.0,
Figure 4). Clearly there is a marked improvement in
CNS penetration with these compounds when the N,N-
dimethylamine group is introduced onto the R-carbon
of 1. As we have shown with the NMR studies previ-
ously described, we believe that the amide hydrogen is
involved in an intramolecular hydrogen bond with the
nitrogen atom of the R-substituent. As hypothesized,
this hydrogen bond removes one of the hydrogen bond
donor moieties and one of the nitrogen acceptor groups.
Both of these groups are hydrophilic portions of the
molecule, and the hydrogen bond has the effect of
making the compound more lipophilic, and thus more
able to cross membranes, such as the blood-brain
barrier, and hence increase the ratio of brain to plasma.
To further substantiate this hypothesis of the devel-
opment of an intramolecular hydrogen bonded com-
pound being more brain penetrant, 11e was compared

2280 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14
Ashwood et al.
F igu r e 3. Representation of 11e with a five-membered hydrogen bonded (yellow line) ring to the urethane (left) and a six-
membered hydrogen bonded (yellow line) ring to the amide (right).
F igu r e 5. Effect of 11e on [Sar9, Met(O2)11]substance P
F igu r e 4. Area under the curve (AUC, 0-1 h) results for
induced foot tapping in the gerbil. Compound 11e (0.1-10 mg/
compounds 1 and 11e in rats (n ) 2) after a 0.5 mg/kg iv
kg) or vehicle was administered 1 h before and 1 (30 mg/kg)
administration.26
0.5 h before 30 nmol [Sar9, Met(O2)11]substance P (icv). The
duration of foot tapping was recorded for 5 min immediately
following anesthesia. Results are shown as the mean (vertical
to 1 in the gerbil foot tapping paradigm as a model of
bars show SEM) of 9-12 animals per group. **P < 0.01,
CNS activity.27 Intracerebroventricularly (icv) admin-
significantly different from the vehicle treated control group
istered Substance P elicits a centrally mediated hind
foot tapping in the gerbil. This effect has been shown
to be antagonized by a centrally penetrating compound
when administered subcutaneously (sc), but not antago-
nized by a peripheral selective compound administered
via the same route of administration, though the
peripheral selective compound can antagonize the effect
when administered icv.27 Compounds 1 and 11e have
very similar in vitro affinities for the gerbil NK1 receptor
(IC50 ) 5.9 and 5.5 nM, respectively) and would be
expected to have a similar pharmacological effect.
(one-way ANOVA followed by Dunnett’s t-test).
demonstrated that following similar administration, 1
antagonizes the foot tapping response with a MED of
10 mg/kg.27 Taking into account the MED’s and mag-
nitude of antagonism, 11e appears to be 10-30-fold
more potent than 1 in this paradigm.
Con clu sion s
We have shown that the R-substituent of 1 can be
modified without any deleterious effect on the in vitro
binding affinity of the compounds for the NK1 receptor
and still show selectivity over the other tachykinin
receptors (11e, hNK2 IC50 ) 671 nM, hNK3 IC50 ) IA).
We have also shown that when the R-substituent
incorporates a heteroatom there is a development of an
intramolecular hydrogen bond to the amide hydrogen,
resulting in the formation of a six-membered hydrogen
bonded ring. The presence of a heteroatom (nitrogen)
in 11e has also been shown to increase the aqueous
solubility, via formation of a salt, of this compound in
comparison with compound 1. The presence of an
intramolecular hydrogen bond has been substantiated
A duration study showed that 11e blocked the [Sar9,
Met(O2)11]substance P induced foot tapping response in
gerbils at 1 h pretreatment time. Compound 1 was used
as a positive control and was administered 0.5 h before
[Sar9, Met(O2)11]substance P. Duration of foot tapping
27
was determined as previously described.
Compound 11e (0.1-10 mg/kg, sc), administered 1 h
before [Sar9, Met(O2)11]substance P (30 nmol/animal,
icv), antagonized the foot tapping response with a
minimum effective dose (MED) of 1 mg/kg (Figure 5).
This dose produced a magnitude of antagonism similar
to that of the 30 mg/kg dose of 1. We have previously

Effects of R-Substitution of an NK1 Receptor Antagonist
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14 2281
for 16 h. The solvent was removed in vacuo, the product was
extracted into EtOAc, and the organics were washed with
water, 10% HCl, and brine and dried (MgSO4). The product
was purified by chromatography (25% EtOAc in heptane) to
give a clear oil (10.39 g, 86%): δH 2.55 (1H, m, CH2), 2.65 (1H,
d, CHH, J ) 13.2 Hz), 3.85 (1H, dd, OCHH, J ) 5.2, 13.2 Hz),
4.01 (1H, t, CH, J ) 7.0 Hz), 4.12 (1H, m, OCHH), 4.69 (1H,
t, R-H, J ) 8.0 Hz), 4.80-5.24 (6H, m, 2 × CH2O, dCH2), 5.50
(1H, m, CHd), 6.51 (1H, d, CH, J ) 6.0 Hz), 6.98 (1H, t, arom,
J ) 7.4 Hz), 7.10 (1H, m, arom), 7.19 (1H, t, arom, J ) 7.6
Hz), 7.27-7.38 (10H, m, arom), 7.63 (1H, bs, arom); νmax 3065,
3033, 1716, 1483, 1416, 1266, 1173, 753 cm-1; m/z 513 (MH+,
by the temperature dependence of the amide proton at
low temperature in the NMR studies, by the increased
brain penetration, and also pharmacologically in the
gerbil foot tapping paradigm, where the increase in
efficacy is indicative of an increase in the brain penetra-
tion.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were determined on
a Mettler FP80 or a Reichert Thermovar hot-stage apparatus.
Proton NMR spectra were recorded on a Varian Unity +400
MHz spectrometer using deuterochloroform as the solvent at
298 K unless otherwise stated; chemical shifts are recorded
in ppm downfield from tetramethylsilane. IR spectra are
recorded with the compound neat on a sodium chloride disk
on a Perkin-Elmer System 2000 Fourier transform spectro-
photometer. Optical rotations were determined with a Perkin-
Elmer 241 polarimeter. Mass spectra were recorded with a
Finnigan MAT TSQ70 or Fisons VG trio-2A instrument.
Accurate mass spectra were obtained from EPSRC Nation
Mass Spectrometry Service Center, Swansea, U.K. Elemental
analyses are within (0.4% of theoretical values and were
determined either by Medac Ltd., Uxbridge, UK., or Butter-
worth, Teddington, U.K. Normal phase silica gel used for
chromatography was Merck no. 9385 (230-400 mesh) supplied
by E. Merck, A. G. Darmstadt, Germany. Anhydrous solvents
were purchased in septum-capped bottles from Fluka Chemi-
cals Ltd., Glossop, U.K.
20
100); [R]D +2.6° (c ) 0.11, MeOH).
(2R,3a S,8a R)-2-P r op yl-2,3,3a ,8a -t et r a h yd r o-p yr r olo-
[2,3-b]in d ole-1,2,8-tr ica r boxylic Acid 2-Allyl Ester 1,8-
Diben zyl Ester (6a ). LHMDS (7.81 mL, 7.81 mmol, 1 M in
THF) was added to a solution of compound 5 (2.00 g, 3.91
mmol) and DMPU (0.47 mL, 3.91 mmol) in THF (30 mL) at
-78 °C under dry N2. After 2 h at this temperature, iodoethane
(1.22 g, 7.81 mmol) was added, and the mixture allowed to
warm to room temperature overnight.19 The solvent was
removed in vacuo, and the product was extracted into EtOAc,
washed with 10% HCl and brine, and dried (MgSO4). Purifica-
tion was achieved by chromatography (15-20 EtOAc in
heptane) to leave a clear oil (1.66 g, 79%): δH 0.81 (3H, t,
CH2CH3, J ) 7.4 Hz), 1.88 (1H, m, CHHCH3), 2.32 (1H, bs,
CHHCH3), 2.46 (1H, dd, IndCHH, J ) 7.4, 13.6 Hz), 2.62 (1H,
d, IndCHH, J ) 13.6 Hz), 3.63 (1H, dd, CHHO, J ) 5.2, 13.6
Hz), 3.87 (1H, t, CH, J ) 6.8 Hz), 4.09 (1H, dd, CHHO, J )
5.6, 13.2 Hz), 5.08 (6H, m, 2 × CH2O, dCH2), 5.39 (1H, m,
dCH), 6.43 (1H, d, CH, J ) 6.0 Hz), 6.99 (1H, t, arom, J ) 7.4
Hz), 7.07 (1H, d, arom, J ) 7.6 Hz), 7.18 (1H, t, arom, J ) 7.6
Hz), 7.27-7.37 (10H, m, arom), 7.55 (1H, d, arom, J ) 7.2 Hz);
νmax 1716, 1482, 1410, 1267, 750 cm-1; HRMS for C32H33N2O6
(R)-2-Ben zyloxyca r bon yla m in o-3-(1H-in d ol-3-yl)-p r o-
p ion ic Acid Allyl Ester (3). A solution of (R)-N-CBZ-
tryptophan (1.00 g, 29.6 mmol), N,N′-dicyclohexylcarbodiimide
(640 mg, 31.1 mmol), N,N-dimethyl-4-aminopyridine (36 mg,
2.96 mmol), and dichloromethane (10 mL) was stirred for 10
min, and then allyl alcohol (0.22 mL, 32.5 mmol) was added.
After 30 min the mixture was filtered and the solvent removed
in vacuo. The product was purified by chromatography (33%
EtOAc in heptane) to yield a clear oil which solidified on
standing. Recrystallization (EtOAc/heptane) gave an amor-
phous solid (1.00 g, 89%): mp 83-85 °C; δH 3.32 (2H, d,
IndCH2, J ) 5.2 Hz), 4.56 (2H, bs, CH2O), 4.74 (1H, dt, R-H,
J ) 7.8, 7.8 Hz), 5.11 (2H, m, CH2O), 5.20-5.32 (3H, m, NH,
dCH2), 5.82 (1H, m, CH), 6.96 (1H, d, arom, J ) 2.0 Hz), 7.08
(1H, t, arom, J ) 7.4 Hz), 7.18 (1H, d, arom, J ) 7.2 Hz), 7.34
(6H, m, arom), 7.52 (1H, d, arom, J ) 8.0 Hz), 8.04 (1H, bs,
NH); νmax 3410, 3361, 3060, 1713, 1512, 1205, 743 cm-1; m/z
requires 541.234, found 541.234 (MH+, 100%); [R]D + 13.5°
20
(c ) 0.80, MeOH).
(2R,3aS,8aR)-2-Allyl-2-bu t-3-en oyl-2,3,3a,8a-tetr ah ydr o-
p yr r olo[2,3-b]in d ole-1,8-d ica r boxylic Acid Diben zyl Es-
ter (6b). Procedure as for the preparation of compound 6a to
give an oil (0.55 g, 26%): δΗ 2.50-2.63 (3H, m, CHHCdC,
CH2), 3.10-3.25 (1H, m, CHHCdC), 3.66 (1H, dd, CHHO, J
) 5.5, 13.3 Hz), 3.85 (1H, t, J ) 6.3 Hz, CH), 4.12 (1H, dd,
CHHO, J ) 7.1, 14.2 Hz), 4.99-5.27 (8H, m, 2 × dCH2, 2 ×
CH2O), 5.36-5.46 (1H, m, dCH), 5.55-5.66 (1H, m, dCH),
6.38 (1H, d, CH, J ) 6.3 Hz), 6.99 (1H, t, J ) 7.3 Hz, arom),
7.07 (1H, d, arom, J ) 7.3 Hz), 7.18 (1H, t, arom, J ) 7.7 Hz),
7.28-7.38 (10H, m, arom), 7.55 (1H, bd, arom, J ) 6.8 Hz);
378 (MH+, 18%), 130 (100%); [R]D +14.5° (c ) 0.75, MeOH).
20
ν
max 1714, 1409, 1273, 750 cm-1; MS (ES+) 576.16 (MH+ + Na,
Anal. (C22H22N2O4) C, H, N.
100%), 553.26 (M+ + H, 99%).
(2r ,3a S,8a S)-3,3a ,8,8a -Tetr a h yd r o-2H-p yr r olo[2,3-b]in -
d ole-1,2-d ica r boxylic Acid 2-Allyl Ester 1-Ben zyl Ester
(4). Compound 3 (17.25 g, 45.6 mmol) was dissolved in
trifluoroacetic acid (100 mL) and stirred at room temperature
for 3 h. The mixture was concentrated (∼50 mL) in vacuo, and
then added dropwise to a well-stirred mixture of NaHCO3
(15%, 1 L) and dichloromethane (500 mL). 19 After the addition,
the organics were washed with saturated NaHCO3 and brine
and dried (MgSO4). The product was purified by chromatog-
raphy (20-50% Et2O in heptane) to yield a clear oil (8.90 g,
52%): δH this compound exhibited rotamers, hence the broad
signals 2.64 (2H, m, CH2), 3.83-4.25 (3H, m, CH, CH2O), 4.58
(0.5H, dd, a-H, J ) 1.9, 8.3 Hz), 4.68 (0.5H, m, R-H), 4.75
(0.5H, bs, 0.5 NH), 5.05-5.26 (4.5H, m, CH2O, dCH2, 0.5 NH),
5.50 (1H, m, CHd), 5.60 (1H, t, CH, J ) 6.4 Hz), 6.58 (1H, m,
arom), 6.67 (1H, m, arom), 7.01 (2H, m, arom), 7.28-7.40 (4H,
(2S,3a S,8a R)-2-(2-Met h yl-a llyl)-2,3,3a ,8a -t et r a h yd r o-
p yr r olo[2,3-b]in d ole-1,2,8-tr ica r boxylic Acid 2-Allyl Es-
ter 1,8-Diben zyl Ester (6c). Procedure as for the preparation
of compound 6a to give an oil (0.46 g, 21%): δΗ 1.65 (3H, s,
CH3), 2.50-2.56 (2H, m, CHHCdC, CHHind), 2.76 (1H, dd,
CHHind, J ) 7.8, 13.9 Hz), 3.2-3.3 (1H, m, CHHCdC), 3.62-
3.68 (1H, m, CHHO), 3.85 (1H, t, J ) 6.8 Hz, CH), 4.13 (1H,
dd, CHHO, J ) 5.3, 12.8 Hz), 4.76-5.23 (8H, m, 2 × dCH2, 2
× CH2O), 5.33-5.43 (1H, m, dCH), 6.43 (1H, d, CH, J ) 6.3
Hz), 7.00 (1H, t, J ) 7.4 Hz, arom), 7.07 (1H, d, arom, J ) 7.3
Hz), 7.18 (1H, t, arom, J ) 7.7 Hz), 7.23-7.35 (10H, m, arom),
7.57 (1H, d, arom, J ) 7.1 Hz); νmax 2950, 1717, 1482, 1410,
1333, 1269, 750 cm-1; MS (ES+) 589 (M+ + Na, 100%), 567
(M+ + H, 99%).
(2S,3a S,8a R)-2-Met h oxym et h yl-2,3,3a ,8a -t et r a h yd r o-
p yr r olo[2,3-b]in d ole-1,2,8-tr ica r boxylic Acid 2-Allyl Es-
ter 1,8-Diben zyl Ester (6d ). Procedure as for the preparation
of compound 6a to give a clear oil (1.66 g, 76%): δH 2.52 (1H,
dd, CHH, J ) 1.2, 13.2 Hz), 2.82 (1H, dd, CHH, J ) 8.0, 13.6
Hz), 3.26 (3H, s, OCH3), 3.58 (1H, d, CHHO, J ) 7.6 Hz), 3.78
(1H, dddd, OCHH, J ) 1.6, 1.6, 5.6, 13.2 Hz), 3.90 (1H, t, CH,
J ) 7.0 Hz), 4.06 (1H, bs, CHHO), 4.17 (1H, dd, OCHH, J )
5.6, 13.2 Hz), 4.96-5.16 (6H, m, 2 × CH2O, dCH2), 5.38 (1H,
m, dCH), 6.44 (1H, d, CH, J ) 6.0 Hz), 6.99 (1H, m, arom),
7.08 (1H, d, arom, J ) 7.2 Hz), 7.19 (1H, t, arom, J ) 7.6 Hz),
m, arom), 7.41 (1H, m, arom); νmax 3400, 1702, 1416, 747 cm-1
;
20
m/z 378 (MH+, 90%), 130 (100%); [R]D -144.9° (c ) 1.62,
MeOH). Anal. (C22H22N2O4) C, H, N.
(2R,3a S,8a R)-3,3a ,8,8a -Tet r a h yd r o-2H -p yr r olo[2,3-b]-
in d ole-1,2-d ica r boxylic Acid 2-Allyl Ester 1-Diben zyl
Ester (5). 20Ben zyl ch lor ofor m a te (8.01 g, 47.0 m m ol, 6.7
m L) w a s a d d ed to a stir r ed m ixtu r e of a m in e 4 (8.90 g,
23.5 m m ol), Na 2CO3‚10H2O (13.43 g, 47.0 m m ol), 1,4-
d ioxa n (100 m L), a n d w a ter (10 m L) a t 0 °C. The resulting
mixture was allowed to warm to room temperature and stirred

2282 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14
Ashwood et al.
7.25-7.34 (10H, m, arom), 7.59 (1H, d, arom, J ) 8.0 Hz); νmax
1717, 1483, 1412, 1335, 1274, 751 cm-1; m/z 557 (MH+, 100%);
[R]D +9.6° (c ) 0.75, MeOH). Anal. (C32H32N2O7) C, H, N.
(2H, dd, CH2O, J ) 12.0, 14.8 Hz), 5.75 (2H, m, dCH, NH),
7.14 (1H, t, arom, J ) 8.0 Hz), 7.28-7.47 (13H, m, arom), 8.15
(1H, bd, arom, J ) 6.4 Hz); νmax 3418, 3352, 1736, 1501, 1456,
20
1399, 1250, 1087, 749 cm-1; m/z 557 (MH+, 100%); [R]D
20
(2S,3aS,8aR)-2-Dim eth ylam in om eth yl-2,3,3a,8a-tetr ah y-
d r o-p yr r olo[2,3-b]in d ole-1,2,8-tr ica r boxylic Acid 2-Allyl
Ester 1,8-Diben zyl Ester (6e). Procedure as for the prepara-
tion of compound 6a to give a clear oil (1.90, 76%): δH 2.23
(6H, s, 2 × CH3), 2.40 (1H, d, IndCHH, J ) 13.2 Hz), 2.66
(1H, d, CHHN, J ) 14.4 Hz); 3.00 (1H, dd, IndCHH, J ) 8.2,
13.4 Hz), 3.29 (1H, bs, CHHN), 3.69 (1H, dddd, OCHH, J )
1.6, 2.9, 5.8, 13.3 Hz), 3.94 (1H, t, CH, J ) 7.0 Hz), 4.11 (1H,
bs, CHHN), 4.93-5.33 (7H, m, 2 × CH2O, dCH, dCH2), 6.40
(1H, d, CH, J ) 6.4 Hz), 6.99 (1H, t, arom, J ) 7.4 Hz), 7.06
(1H, d, arom, J ) 7.6 Hz), 7.18 (1H, t, arom, J ) 7.6 Hz), 7.26-
7.37 (10H, m, arom), 7.58 (1H, bs, arom); νmax 2947, 1717, 1483,
1412, 1331, 1267, 1043, 1020, 750 cm-1; HRMS for C33H36N3O6
+13.0° (c ) 0.67, MeOH).
3-((S)-Allyloxyca r bon yl-ben zyloxyca r bon yla m in o-(d i-
m eth yla m in o)-p r op yl)-in d ole-1-ca r boxylic Acid Ben zyl
Ester (7e). A solution of compound 6 (5.82 g, 10.2 mmol) in
methanol (20 mL) was treated with a mixture of cH2SO4/H2O
(23/18 mL), and the resultant mixture was stirred at room
temperature for 24 h. This solution was added dropwise to a
mixture of saturated NaHCO3 and ice, the product was
extracted with EtOAc, and the organics were washed with
saturated NaHCO3 and brine and dried (MgSO4). The material
was purified by chromatography (10-25% EtOAc in heptane)
to give a straw colored gum (3.46 g, 59%): δH 2.26 (6H, s, 2 ×
CH3), 2.83 (1H, d, CHHN, J ) 13.6 Hz), 3.23 (1H, d, IndCHH,
J ) 14.4 Hz), 3.32 (1H, d, CHHN, J ) 13.6 Hz), 3.64 (1H, dd,
IndCHH, J ) 14.4 Hz), 4.49 (1H, d, CHHO, J ) 13.2 Hz), 4.59
(1H, d, CHHO, J ) 6.0 Hz), 5.08 (2H, dd, CH2O, J ) 12.4,
27.6 Hz), 5.23 (1H, d, dCHH, J ) 10.4 Hz), 5.34 (1H, d, d
CHH, J ) 14.4 Hz), 5.41 (2H, s, CH2O), 5.85 (1H, m, dCH),
6.00 (1H, s, NH), 7.14 (2H, m, arom), 7.25-7.48 (12 H, m,
arom), 8.15 (1H, bd, arom, J ) 6.4 Hz); νmax 3418, 1736, 1456,
19
requires 570.2604, found 570.2604 (MH+, 100%); [R]D -0.4°
(c ) 0.49, MeOH).
3-((R)-2-Allyloxyca r bon yl-2-ben zyloxyca r bon yla m in o-
bu tyl)-in d ole-1-ca r boxylic Acid Ben zyl Ester (7a ). TFA
(2 mL) was added to a solution of compound 6a (1.66 g, 3.07
mmol) in dichloromethane (10 mL), and the resulting solution
was stirred at room temperature for 24 h. The solvent was
removed, and the residue was diluted with EtOAc, the organics
were washed with saturated NaHCO3 and brine and dried
(MgSO4). The product was purified by chromatography (15%
EtOAc in heptane) to yield a clear gum (1.14 g, 69%): δH 0.82
(3H, t, CH2CH3, J ) 7.4 Hz), 1.99, 2.60 (2H, 2 × m, CH2CH3),
3.23 (1H, d, IndCHH, J ) 10.4 Hz), 3.74 (2H, d, IndCHH, J )
10.4 Hz), 4.46 (1H, d, OCHH, J ) 6.0 Hz), 4.57 (1H, d, CHHO,
J ) 12.8 Hz), 5.09 (2H, dd, CH2O, J ) 12.4, 18.4 Hz), 5.21
(1H, d, dCHH, J ) 14.4 Hz), 5.30 (1H, d, dCHH, J ) 10.4
Hz), 5.41 (2H, dd, CHHO, J ) 12.4, 16.8 Hz), 5.74 (1H, s, NH),
5.80 (1H, m, dCH), 7.11 (1H, t, arom, J ) 7.6 Hz), 7.25-7.47
(13H, m, arom), 8.17 (1H, bd, arom, J ) 5.6 Hz); νmax 3419,
1736, 1500, 14456, 1399, 1250, 1085 cm-1; HRMS for C32H33N2-
O6 requires 541.234, found 541.234 (MH+, 100%); [R]D20 +8.1°
(c ) 0.57, MeOH).
3-((R)-2-Allyloxyca r bon yl-2-ben zyloxyca r bon yla m in o-
p en t-4-en yl)-in d ole-1-ca r boxylic Acid Ben zyl Ester (7b).
Procedure as for the preparation of compound 7a to give an
oil (0.48 g, 92%): δΗ 2.66-2.72 (1H, m, CHHCd), 3.26 (1H, d,
CHHind, J ) 14.4 Hz), 3.27-3.35 (1H, m, CHHCd), 3.77 (1H,
d, CHHind, J ) 14.4 Hz), 4.43-4.48 (1H, m, OCHH), 4.55 (1H,
dd, OCHH, J ) 5.7, 13.1 Hz), 5.03-5.12 (4H, m, OCH2, dCH2),
5.20 (1H, d, dCH, J ) 10.3 Hz), 5.29 (1H, d, dCHH, J ) 17.1
Hz), 5.37-45 (2H, m, CH2Ph), 5.57-5.67 (1H, m, dCH), 5.72
(1H, s, NH), 7.12 (1H, t, arom, J ) 7.6 Hz) 7.26-7.48 (13H,
m, arom), 8.12 (1H, bd, arom, J ) 4.9 Hz); νmax 3416, 1736,
1455, 1249, 1083, 748 cm-1; MS (ES+) 575.29 (M+ + Na, 63%),
553.32 (M+ + H, 100%).
3-((R)-2-Allyloxyca r bon yl-2-ben zyloxyca r bon yla m in o-
4-m eth yl-p en t-4-en yl)-in d ole-1-ca r boxylic Acid Ben zyl
Ester (7c). Procedure as for the preparation of compound 7a
to give an oil (0.33 g, 79%): δΗ 1.63 (3H, s, CH3), 2.70 (1H, d,
CHHCdC, J ) 13.9 Hz), 3.23 (1H, d, CHHind, J ) 14.4 Hz),
3.41 (1H, d, CHHCdC, J ) 13.8 Hz), 3.87 (1H, d, CHHind, J
) 14.4 Hz), 4.41-4.53 (2H, m, OCH2), 4.70 (1H, s, CHHdC),
4.80 (1H, s, CHHdC), 5.02 (1H, d, CHHPh, J ) 12.2 Hz), 5.11
(1H, d, CHHPh, J ) 12.2 Hz), 5.30 (1H, d, dCHH, J ) 17.7
Hz), 5.41 (2H, dd, CH2Ph, J ) 12.2, 15.9 Hz), 5.78-5.86 (2H,
m, NH, dCH), 7.12 (1H, t, arom, J ) 7.4 Hz) 7.25-7.49 (13H,
m, arom), 8.13 (1H, bs, arom); νmax 3418, 2946, 1722, 1498,
1455, 1398, 1358, 1249, 1083, 1048, 747 cm-1; MS (ES+) 589
(M+ + Na, 100%), 567 (M+ + H, 43%).
1248, 1084, 1037, 748 cm-1; m/z 570 (MH+, 100%); [R]D
-12.6° (c ) 0.27, MeOH).
19
3-((R)-2-Ben zyloxyca r bon yla m in o-2-ca r boxy-bu tyl)-in -
d ole-1-ca r b oxylic Acid Ben zyl E st er (8a ). Tetrakis(tri-
phenylphosphine)palladium (0) (50 mg, 43 µmol) was added
to a solution of compound 7a (1.14 g, 2.11 mmol) in THF (10
mL). After 5 min, morpholine (1.84 g, 21.1 mmol) was added,
and the mixture stirred at room temperature for 30 min.
EtOAc was added, and the organics were washed with 10%
HCl and brine and dried (MgSO4). After removal of the solvent
in vacuo, a clear glass was obtained (1.01 g, 95%): δH 0.86
(3H, t, CH2CH3, J ) 7.6 Hz), 1.99 (1H, m, CHHCH3), 2.51 (1H,
m, CHHCH3), 3.30 (1H, d, IndCHH, J ) 14.9 Hz), 3.71 (1H, d,
IndCHH, J ) 14.4 Hz), 5.07 (2H, dd, CH2O, J ) 12.4, 19.2
Hz), 5.40 (2H, s, CH2O), 5.60 (1H, s, NH), 7.10 (1H, t, arom, J
) 7.4 Hz), 7.24-7.52 (13H, m, arom), 8.10 (1H, bs, arom); νmax
3409, 1732, 1455, 1400, 1250, 1086, 745 cm-1; HRMS for
C
29H29N2O6 requires 501.2026, found 501.2026 (MH+).
3-((R)-2-Ben zyloxyca r b on yla m in o-2-ca r b oxy-p en t -4-
en yl)-in d ole-1-ca r boxylic Acid Ben zyl Ester (8b). Proce-
dure as for the preparation of compound 8a to give a solid (0.44
g, 98%): δΗ 2.67-2.73 (1H, m, CHHCHd), 3.20-3.26 (1H, m,
CHHCHd), 3.32 (1H, d, CHHInd, J ) 14.7 Hz), 3.73 (1H, d,
CHHind, J ) 14.4 Hz), 5.03-5.12 (4H, m, 2 × OCH2, 2 × d
CH2), 5.39 (2H, s, OCH2Ph), 5.61-5.68 (2H, s, NH, CHd), 7.10
(1H, t, arom, J ) 7.6 Hz), 7.23-7.65 (13H, m, arom), 8.11 (1H,
br s, arom); νmax 3405, 1731, 1455, 1399, 1249, 1084, 747 cm-1
MS (ES-) 511 (M- - H, 100%).
;
3-((R)-2-Ben zyloxyca r bon yla m in o-2-ca r boxy-4-m eth yl-
p en t-4-en yl)-in d ole-1-ca r boxylic Acid Ben zyl Ester (8c).
Procedure as for the preparation of compound 8a to give a solid
(0.28 g, quantitative): δΗ 1.65 (3H, s, CH3), 2.71 (1H, d,
CHHCHd, J ) 13.7 Hz), 3.27 (1H, d, CHHind, J ) 14.9 Hz),
3.35 (1H, d, CHHCd, J ) 13.9 Hz), 3.84 (1H, d, CHHind, J )
14.9 Hz), 4.74 (1H, s, CdCHH), 4.80 (1H, s, CdCHH), 5.02
(1H, d, OCHHPh, J ) 12.2 Hz), 5.11 (1H, d, OCHHPh, J )
12.5 Hz), 5.39 (2H, s, OCH2Ph), 5.79 (1H, s, NH), 7.09 (1H, t,
arom, J ) 7.3 Hz), 7.23-7.65 (13H, m, arom), 8.11 (1H, br s,
arom); νmax 3408, 3033, 2948, 1731, 1500, 1455, 1399, 1358,
1248, 1083, 747 cm-1; MS (ES-) 526 (M-, 33%), 525 (M- - H,
100%).
3-((S)-2-Allyloxyca r bon yl-2-ben zyloxyca r bon yla m in o-
3-m eth oxy-p r op yl)-in d ole-1-ca r boxylic Acid Ben zyl Es-
ter (7d ). Procedure as for the preparation of compound 6a to
give a clear oil (1.19 g, 72%): δH 3.32 (3H, s, OCH3), 3.24 (1H,
d, IndCHH, J ) 14.4 Hz), 3.60 (1H, d, IndCHH, J ) 14.4 Hz),
3.77 (1H, d, CHHO, J ) 9.2 Hz), 4.13 (1H, d, CHHO, J ) 9.2
Hz), 4.49 (1H, dd, OCHH, J ) 4.8, 12.8 Hz), 4.61 (1H, dd,
OCHH, J ) 5.2, 12.8 Hz), 5.09 (2H, s, CH2O), 5.11 (1H, d, d
CHH, J ) 10.8 Hz), 5.28 (1H, d, dCHH, J ) 17.2 Hz), 5.41
3-((S)-2-Ben zyloxycar bon ylam in o-2-car boxy-3-m eth oxy-
p r op yl)-in d ole-1-ca r boxylic Acid Ben zyl Ester (8d ). Pro-
cedure as for the preparation of 8a to give a clear glass (1.11
g, 100%): δH 3.33 (1H, d, IndCHH, J ) 14.7 Hz), 3.37 (3H, s,
OCH3), 3.60 (1H, d, IndCHH, J ) 14.4 Hz), 3.84 (1H, d, CHHO,
J ) 9.3 Hz), 3.99 (1H, d, CHHO, J ) 8.8 Hz), 5.09 (2H, s,
CH2O), 5.40 (2H, s, CH2O), 5.71 (1H, s, NH), 7.14 (1H, t, arom,
J ) 7.6 Hz), 7.27-7.52 (13H, m, arom), 8.18 (1H, dd, arom, J
) 6.8 Hz); νmax 3411, 1732, 1456, 1399, 1250, 1086, 748 cm-1
.

Effects of R-Substitution of an NK1 Receptor Antagonist
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14 2283
3-((S)-Ben zyloxycar bon ylam in o-car boxy-(dim eth ylam i-
n o)-p r op yl)-in d ole-1-ca r boxylic Acid Ben zyl Ester (8e).
Procedure as for the preparation of compound 8a to give a
straw colored foam (690 mg, quant.): δH 2.55 (6H, bs, N(CH3)2),
2.60 (2H, bs, CH2N), 3.20, 3.46 (2H, dd, CH2Ind, J ) 14.0 Hz),
4.90 (2H, d, CH2O, J ) 12.0, 58.4 Hz), 5.36 (2H, dd, CH2O, J
) 12.4, 26.0 Hz), 6.45 (1H, s, NH), 7.08 (1H, bs, arom), 7.18-
7.70 (13H, m, arom), 8.10 (1H, bs, arom); νmax 3373, 1731, 1633,
1485, 1456, 1401, 1358, 1249, 1085, 748 cm-1; HRMS for
CHCH3, J ) 7.2, 7.2 Hz), 5.02 (2H, dd, CH2O, J ) 12.4, 28.8
Hz), 5.40 (2H, s, CH2O), 6.40 (1H, s, NH), 7.15-7.55 (19H, m,
arom, NH), 8.16 (H, s, arom), 8.28 (1H, s, arom); νmax 3373,
1732, 1666, 1486, 1250, 1077, 747 cm-1; m/z 633 (MH+, 100%),
486 (37%); [R]D20 -34.6° (c ) 0.36, MeOH). Anal. (C38H40N4O5)
C, H, N.
(R)-2-Am in o-2-(1H-in d ol-3-ylm et h yl)-N-((S)-1-p h en yl-
eth yl)-bu tyr a m id e (10a ). A mixture of compound 9a (980
mg, 1.63 mmol), 10% palladium hydroxide on carbon, and
methanol (20 mL) was hydrogenated at 50 psi at 30 °C. After
90 min, the mixture was filtered through Kieselguhr, and upon
removal of the solvent in vacuo a clear glass was obtained (503
mg, 92%): δH 0.97 (3H, t, CH2CH3, J ) 7.4 Hz), 1.42 (3H, d,
CHCH3, J ) 6.8 Hz), 1.55 (3H, m, CHHCH3, NH2), 2.10 (1H,
m, CHHCH3), 2.78 (1H, d, IndCHH, J ) 14.0 Hz), 3.46 (1H, d,
IndCHH, J ) 14.0 Hz), 5.06 (1H, dq, CHCH3, J ) 7.2, 7.2 Hz),
6.71 (1H, bs, NH), 7.07-7.35 (8H, m, arom), 7.60 (1H, d, arom,
J ) 19.6 Hz), 7.80 (1H, d, arom, J ) 7.6 Hz), 7.86 (2H, bs,
NH); νmax 3294, 1644, 1512, 1456, 743 cm-1; HRMS for
C21H26N3O1 requires 336.2076, found 336.2076 (MH+).
C
30H32N3O6 requires 530.229, found 530.229 (MH+).
3-[(R)-2-Ben zyloxyca r bon yla m in o-2-((S)-1-p h en yl-eth -
ylca r ba m oyl)-bu tyl]-in d ole-1-ca r boxylic Acid Ben zyl Es-
ter (9a ). A mixture of compound 8a (1.01 g, 2.02 mmol), HBTU
(766 mg, 2.02 mmol), and DIPEA (0.70 mL, 2.02 mmol) in DMF
(10 mL) was stirred at room temperature for 10 min. Then
(S)-methylbenzylamine (244 mg, 2.02 mmol) and DIPEA (0.70
mL, 2.02 mmol) were added, and the resulting solution was
stirred for 8 h. The solvent was removed, and the product was
extracted into EtOAc, washed with 10% HCl, 10% K2CO3, and
brine, and dried (MgSO4). Purification by chromatography gave
a clear glass which was recrystallized (EtOAc/heptane) to yield
white crystals (980 mg, 80%): δH 0.77 (3H, t, CH2CH3, J )
7.4 Hz), 1.26 (3H, d, CHCH3, J ) 6.8 Hz), 1.74 (1H, m,
CHHCH3), 2.40 (1H, m, CHHCH3), 3.31 (1H, d, IndCHH, J )
14.9 Hz), 3.54 (1H, d, IndCHH, J ) 14.9 Hz), 4.99 (1H, dq,
CHCH3, J ) 7.0, 8.5 Hz), 5.04 (2H, dd, PhCH2O, J ) 13.0,
27.2 Hz), 5.42 (2H, s, CH2O), 5.83 (1H, bs, NH), 6.01 (1H, d,
NH, J ) 7.6 Hz), 7.17-7.55 (19H, m, arom), 8.15 (1H, d, arom,
J ) 6.4 Hz); νmax 3346, 1728, 1644, 1485, 1455, 1399, 1249,
1079, 747 cm-1; m/z 604.4 (MH+, 100%); [R]D20 -38.1° (c ) 0.48,
MeOH). Anal. (C37H37N3O5) C, H, N.
3-[(R)-2-Ben zyloxyca r bon yla m in o-2-((S)-1-p h en yl-eth -
ylca r ba m oyl)-p en t-4-en yl]-in d ole-1-ca r boxylic Acid Ben -
zyl Ester (9b). Procedure as for the preparation of compound
9a to give a white solid (295 mg, 61%): δΗ 1.30 (3H, d, CHCH3,
J ) 6.8 Hz), 2.65-2.89 (2H, m, CH2CHd), 3.37-3.50 (2H, m,
CH2Ind), 4.97-5.10 (5H, m, dCH2, CH2O, CHCH3), 5.38-5.45
(2H, m, OCH2), 5.59-5.68 (2H, m, NHZ, CHd), 6.25 (1H, d,
NHCO, J ) 7.1 Hz), 6.29 (1H, m, NH), 7.13-7.55 (19H, m,
arom), 8.16 (1H, bs, arom); νmax 3335, 1727, 1643, 1484, 1455,
1398, 1249, 1083, 747 cm-1; MS (ES-) 615 (M-, 50%), 614 (M-
- H, 100%); 2:1 mixture of diastereomers.
(R)-2-Am in o-2-(1H-in d ol-3-ylm eth yl)-p en t-4-en oic Acid
((S)-1-p h en yl-eth yl)-a m id e (10b). Procedure as for the
preparation of compound 10a to give a white solid (100 mg
65%): δΗ 0.93 (3H, d, CH3, J ) 7.2 Hz), 1.13-1.54 (5H, m, 3
× CH, NH2), 1.42 (3H, d, CH3, J ) 6.8 Hz), 2.76 (1H, d,
CHHInd, J ) 14.2 Hz), 3.48 (1H, d, CHHInd, J ) 14.2 Hz),
5.01-5.09 (1H, m, CHCH3), 6.69 (1H, d, NH, J 2.0 Hz), 7.04-
7.37 (8H, m, arom, NH), 7.59 (1H, d, arom, J ) 8.1 Hz), 7.80-
7.82 (1H, m, arom), 8.02 (1H, s, NH); νmax 3296, 1644, 1510,
1455, 742 cm-1; MS (ES+) 699 (2M + H+, 100%), 372 (M+
+
Na), 350 (MH +); 2:1 mixture of diastereomers only peaks for
major diastereomer shown.
(R)-2-Am in o-2-(1H-in d ol-3-ylm eth yl)-4-m eth yl-p en t-4-
a n oic Acid ((S)-1-p h en yl-eth yl)-a m id e (10c). Procedure as
for the preparation of compound 10a to give a white solid (130
mg 98%): δΗ 0.77 (3H, d, CH3, J ) 6.6 Hz), 0.97 (3H, d, CH3,
J ) 6.6 Hz), 1.24 (3H, d, CH3, J ) 6.8 Hz), 1.38-1.49 (1H, m,
CHHCH(CH3)2), 1.60-1.69 (1H, m, CH(CH3)2), 2.02-2.12 (1H,
m, CHHCH(CH3)2), 2.71(1H, d, CHHInd, J ) 13.9 Hz), 3.47
(1H, d, CHHInd, J ) 13.6 Hz), 5.00-5.06 (1H, m, NHCH), 6.67
(1H, d, arom, J ) 2.2 Hz), 7.02-7.38 (8H, m, arom), 7.60 (1H,
d, arom, J ) 7.8 Hz), 7.79-7.82 (1H, m, arom) 8.16 (1H, s,
NH); νmax 3293, 2954, 2927, 2869, 1646, 1508, 1455, 1341, 1212,
1159, 1124, 1104, 1010, 878, 807, 746 cm-1; MS (ES+) 727 (2M+
+ H, 100%), 364 (M+ + H, 53%).
3-[(R)-2-Ben zyloxyca r b on yla m in o-4-m et h yl-2-((S)-1-
p h en yl-et h ylca r b a m oyl)-p en t -4-en yl]-in d ole-1-ca r b ox-
ylic Acid Ben zyl Ester (9c). Procedure as for the prepara-
tion of compound 9a to give a white solid (0.24 g 74%): δΗ
1.27 (3H, d, CHCH3, J ) 6.8 Hz), 1.59 (3H, s, dCCH3), 2.61
(1H, d, CHHCd, J ) 14.2 Hz), 2.95-3.01 (1H, m, CHHCd),
3.32-3.60 (2H, m, CH2Ind), 4.56-4.77 (2H, 2 × s, dCH2),
4.90-5.12 (3H, m, OCH2, CHCH3), 5.42 (2H, s, OCH2), 5.82
(1H, s, NHZ), 6.21 (1H, d, NHCO, J ) 7.1 Hz), 7.08-7.56 (19H,
m, arom), 8.16 (1H, bs, arom); νmax 3355, 1727, 1640, 1484,
1455, 1398, 1358, 1249, 1078, 746 cm-1; MS (ES-) 629 (M-,
42%), 628 (M- - H,100%).
(S)-2-Am in o-3-(1H-in d ol-3-yl)-2-m eth oxym eth yl-N-((S)-
1-p h en yl-eth yl)-p r op ion a m id e (10d ). Procedure as for the
preparation of compound 10a to give a pink colored foam (630
mg, quant.): δH (DMSO-d6) 1.36 (3H, d, CHCH3, J ) 6.8 Hz),
3.26 (3H, s, OCH3), 3.37 (2H, s, IndCH2), 3.66 (1H, d, CHHO,
J ) 10.0 Hz), 4.17 (1H, d, CHHO, J ) 10.0 Hz), 4.90 (1H, dq,
CHCH3, J ) 6.8, 6.8 Hz), 7.00-7.38 (8H, m, arom), 7.70 (1H,
d, arom, J ) 7.6 Hz), 8.17 (3H, bs, NH, NH2), 8.94 (1H, d, arom,
J ) 7.6 Hz), 11.17 (1H, d, NH, J ) 1.2 Hz); νmax 3419, 3213,
3057, 1667, 1494, 1458, 1106, 746 cm-1; HRMS for C21H26N3O2
3-[(S)-2-Ben zyloxyca r bon yla m in o-3-m eth oxy-2-((S)-1-
ph en yl-eth ylcar bam oyl)-pr opyl]-in dole-1-car boxylic Acid
Ben zyl Ester (9d ). Procedure as for the preparation of
compound 8a to give a clear glass (1.04 g, 78%): δH 1.37 (3H,
d, CHCH3, J ) 6.8 Hz), 3.35 (3H, s, OCH3), 3.39 (1H, d,
IndCHH, J ) 15.2 Hz), 3.47 (1H, d, CHHO, J ) 9.2 Hz), 3.66
(1H, d, IndCHH, J ) 14.4 Hz), 4.16 (1H, d, CHHO, J ) 8.0
Hz), 4.98 (1H, m, CHCH3), 5.03 (2H, bs, CH2O), 5.40 (2H, bs,
CH2O), 6.02 (1H, bs, NH), 7.14-7.53 (20 H, m, arom, NH),
8.14 (1H, bs, arom); νmax 3350, 1732, 1653, 1488, 1455, 1398,
requires 352.2025, found 352.2025 (MH+); [R]D -9.2° (c )
19
0.66, MeOH). Anal. (C21H25N3O2‚0.4 H2O) C, H, N.
(S)-2-Am in o-2-d im eth yla m in om eth yl-3-(1H-in d ol-3-yl)-
N-((S)-1-p h en yl-eth yl)-p r op ion a m id e (10e). Procedure as
for the preparation of compound 10a to give a clear glass (342
mg, quant.): δH 1.42 (3H, d, CHCH3, J ) 7.2 Hz), 2.32 (6H, s,
N(CH3)2), 2.46 (1H, d, CHHN, J ) 12.4 Hz), 2.83 (1H, d,
CHHInd, J ) 14.0 Hz), 3.13 (1H, d, CHHN, J ) 12.4 Hz), 3.20
(1H, d, CHHInd, J ) 14.0 Hz), 5.00 (1H, dq, CHCH3, J ) 7.2,
7.2 Hz), 6.74 (1H, s, arom), 7.03-7.25 (6H, m, arom), 7.33 (1H,
d, arom, J ) 8.0 Hz), 7.61 (1H, d, arom, J ) 8.0 Hz), 8.14 (1H,
d, CONH, J ) 8.0 Hz), 8.42 (1H, s, NH); HRMS for C22H29N4O
1249, 1084, 748 cm-1; m/z 620 (MH+, 100%); [R]D -21.7° (c
20
) 0.53, MeOH). Anal. (C37H37N3O6) C, H, N.
3-[(S)-Ben zyloxyca r bon yla m in o-(d im eth yla m in o)-((S)-
1-p h en yl-et h ylca r b a m oyl)-p r op yl]-in d ole-1-ca r b oxylic
Acid Ben zyl Ester (9e). Procedure as for the preparation of
compound 8a to afford white crystals (EtOAc/heptane) (150
mg, 34%): mp 102-107 °C; δH 1.38 (3H, d, CHCH3, J ) 6.8
Hz), 2.14 (6H, s, 2 × CH3), 2.43 (1H, d, CHHN, J ) 14.4 Hz),
3.35 (1H, d, CHHN, J ) 14.4 Hz), 3.38 (1H, d, IndCHH, J )
15.2 Hz), 3.63 (1H, d, IndCHH, J ) 15.2 Hz), 4.98 (1H, dq,
requires 365.2341, found 365.2341 (MH+); [R]D +4.5° (c )
19
0.56, MeOH).
[(R)-1-(1H-In d ol-3-ylm eth yl)-1-((S)-1-p h en yl-eth ylca r -
ba m oyl)-p r op yl]-ca r ba m ic Acid Ben zofu r a n -2-yl Meth yl
Ester (11a ). Compound 10a (503 mg, 1.50 mmol), (2-benzo-
furanyl)methyl 4-nitrophenyl carbonate7 (470 mg, 1.50 mmol),
and DMAP (200 mg) in DMF (10 mL) were stirred at room

2284 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 14
Ashwood et al.
temperature for 7 days. The solvent was removed in vacuo and
the product extracted into EtOAc. The organics were washed
with 10% HCl, 10% K2CO3, and brine and dried (MgSO4).
Purification by chromatography (25-30% EtOAc in heptane)
gave a white foam (167 mg, 22%): mp 69-72 °C; δH 0.80 (3H,
t, CH2CH3, J ) 7.6 Hz), 1.22 (3H, d, CHCH3, J ) 7.6 Hz), 1.87,
2.40 (2H, 2 × m, CH2CH3), 3.45 (2H, dd, IndCH2, J ) 15.2,
32.4 Hz), 4.96 (1H, dq, CHCH3, J ) 6.8, 6.8 Hz), 5.19 (2H, s,
CH2O), 5.83 (1H, s, NH), 6.01 (1H, d, NH, J ) 7.2 Hz), 6.74
(1H, s, arom), 6.84 (1H, d, arom, J ) 7.0 Hz), 7.06 (1H, t, arom,
J ) 6.6 Hz), 7.14-7.32 (9H, m, arom), 7.46 (1H, d, arom, J )
8.0 Hz), 7.58 (2H, m, arom), 7.86 (1H, s, NH); νmax 3357, 2972,
1720, 1649, 1489, 1454, 1073, 742 cm-1; HRMS for C31H32N3O4
60 °C; δH 1.40 (3H, d, CHCH3, J ) 8.4 Hz), 2.16 (6H, s, 2 ×
CH3), 2.50 (1H, d, CHHN, J ) 13.7 Hz), 3.29 (1H, d, CHHN,
J ) 13.7 Hz), 3.54 (2H, dd, IndCH2, J ) 14.7, 26.9 Hz), 5.00
(1H, q, CHCH3, J ) 6.8 Hz), 5.21 (2H, s, CH2O), 6.47 (1H, bs,
NH), 6.76 (1H, s, arom, J ) 7.2 Hz), 6.79 (1H, d, arom, J )
2.4 Hz), 7.04 (1H, t, arom, J ) 7.4 Hz), 7.12 (1H, t, arom, J )
7.0 Hz), 7.23-7.25 (8H, m, arom), 7.49 (1H, d, arom, J ) 8.4
Hz), 7.56 (2H, bd, arom, J ) 7.6 Hz), 7.64 (1H, bs, NH), 8.17
(1H, bs, NH); νmax 3360, 1716, 1652, 1488, 1455, 741 cm-1; m/z
539 (MH+, 100%), 391 (46%). Anal. (C32H34N4O4) C, H, N.
Further characterized as the HCl salt: mp 192-197 °C
23
(IPA); [R]D -89.9° (c ) 0.50, MeOH).
requires 510.2393, found 510.2393 (MH+); [R]D -32.2° (c )
20
0.35, MeOH). Anal. (C31H31N3O4‚0.2H2O) C, H, N.
Ack n ow led gm en t. The authors acknowledge the
help of Nirmala Suman-Chauhan for providing the
receptor binding affinity studies, J ane McGuffog for
providing the solubility data, Giles Ratcliffe for help
with the NMR studies, and Dorica Naylor for the
molecular modeling.
[(R)-1-(1H-In d ol-3-ylm eth yl)-1-((S)-1-p h en yl-eth ylca r -
b a m oyl)-b u t -3-en yl]-ca r b a m ic Acid Ben zofu r a n -2-yl-
m eth yl Ester (11b). A solution of 2-benzofuranylmethanol
(40 mg, 258 µmol) in EtOAc (1 mL) at 0 °C under dry N2 was
treated with triphosgene (33 mg, 110 µmol) followed by DIPEA
(59 µL, 341 µmol). After 30 min, the reaction mixture was
filtered, and the filtrate was treated with compound 10b (90
mg, 258 µmol) and allowed to warm to room temperature and
stirred for 30 min. The mixture was diluted with EtOAc and
washed with 10% K2CO3 and brine and dried (MgSO4). The
crude material was purified by chromatography (0-30%
EtOAc in heptane) to give a white foam (20 mg, 16%): δH 0.84
(3H, d, CHCH3, J ) 7.3 Hz), 1.04-1.14 (1H, m, CH), 1.22 (3H,
d, CH3, J ) 7.2 Hz), 1.20-1.37 (1H, m, CH), 1.72-1.81 (1H,
m, CH), 2.20-2.37 (1H, m, CH), 3.40 (1H, d, CHH, J ) 14.9
Hz), 3.51 (1H, d, CHH, J ) 15.1 Hz), 4.94 (1H, dq, CHCH3, J
) 7.1, 7.1 Hz), 5.15-5.22 (2H, m, CH2O), 5.85 (1H, s, NH),
6.04 (1H, s, NH, J ) 7.6 Hz), 6.72 (1H, s, arom), 6.83 (1H, d,
arom, J ) 2.4 Hz), 7.03-7.07 (1H, m, arom), 7.10-7.32 (9H,
m, arom), 7.45-7.56 (3H, m, arom), 7.86 (1H, bs, NH); νmax
Refer en ces
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tion and Membrane Signalling Mechanisms. Neurochem. Int.
1991, 18, 149-65.
(2) Maggi, C. A.; Patacchini, R.; Rovero, P.; Giachetti, A. Tachykinin
Receptors and Tachykinin Receptor Antagonists. J . Auton.
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(3) Gao, Z.; Peet, N. P. Recent Advances in Neurokinin Receptor
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3354, 2961, 1716, 1650, 1489, 1454, 133, 1067, 741 cm-1
;
(6) Leroy, V.; Mauser, P.; Gao, Z.; Peet, N. P. Neurokinin Receptor
Antagonists. Expert Opin. Invest. Drugs 2000, 9, 735-746.
(7) Boyle, S.; Guard, S.; Higginbottom, M.; Horwell, D. C.; Howson,
W.; McKnight, A. T.; Martin, K.; Pritchard, M. C.; O’Toole, J .;
Raphy, J .; Rees, D. C.; Roberts, E.; Watling, K. J .; Woodruff, G.
N.; Hughes, J . Rational Design of High Affinity Tachykinin NK1
Receptor Antagonists. Bioorg. Med. Chem. 1994, 2, 357-370.
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D. C. Tachykinin Antagonists. U.S. Patent 5 594 022.
(9) Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J .
Experimental and Computational Approaches to Estimate Solu-
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(10) Horwell, D. C.; Lewthwaite, R. A.; Pritchard, M. C.; Ratcliffe,
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tional Restriction of Biologically Active Peptoids. Tetrahedron
1998, 54, 4591-4606.
HRMS for C32H34N3O4 requires 524.2551, found 524.2549
(MH+); 3:2 mixture of diastereomers, only peaks for major
25
diastereomers shown; [R]D -7.2° (c ) 0.29, CHCl3). Anal.
(C32H33N3O4) C, H, N.
[(R)-1-(1H-In d ol-3-ylm eth yl)-3-m eth yl-1-((S)-1-p h en yl-
et h ylca r ba m oyl)-b u t yl]-ca r b a m ic Acid Ben zofu r a n -2-
ylm eth yl Ester (11c). Procedure as for the preparation of
compound 11b to give a white foam: δH 0.69 (3H, d, CHCH3,
J ) 6.4 Hz), 0.86 (3H, d, CH3, J ) 6.4 Hz), 1.15 (3H, d, CH3,
J ) 7.2 Hz), 1.61 (1H, m, CHH), 2.48 (1H, m, CHH), 3.29 (1H,
d, CHH, J ) 15.2 Hz), 3.61 (1H, d, CHH, J ) 15.2 Hz), 4.88
(1H, dq, CHCH3, J ) 7.2, 7.2 Hz), 5.19 (2H, dd, CH2O, J )
13.2, 16.8 Hz), 5.86 (1H, d, NH, J ) 7.2 Hz), 6.22 (1H, s, NH),
6.72 (1H, s, arom), 6.88 (1H, d, arom, J ) 2.0 Hz), 7.04-7.32
(10H, m, arom), 7.46 (1H, d, arom, J ) 8.0 Hz), 7.55 (2H, m,
arom, J ) 6.8 Hz), 7.83 (1H, bs, NH); νmax 3354, 1714, 1645,
1488, 741 cm-1; m/z 537.85 (M+, 100%); [R]D25 -23.1° (c ) 0.64,
CHCl3). Anal. (C33H35N3O4) C, H, N.
(11) Sybil 6.6, Tripos Associates, 1699 South Hanley Road, Suite 303,
St. Louis, MO 63144.
(12) Turk, J .; Panse, G. T.; Marshall G. R. R-Methyl Amino Acids.
Resolution and Amino Protection. J . Org. Chem. 1975, 40, 953-
955.
[(S)-2-(1H-In d ol-3-yl)-1-m eth oxym eth yl-1-((S)-1-p h en -
yl-eth ylca r ba m oyl)-eth yl]-ca r ba m ic Acid Ben zofu r a n -2-
ylm eth yl Ester (11d ). Procedure as for the preparation of
compound 11b to give a white foam (436 mg, 46%): mp 63-
66 °C; δH 1.40 (3H, d, CHCH3, J ) 6.8 Hz), 3.37 (3H, s, OCH3),
3.46 (1H, d, IndCHH, J 1.2 Hz), 3.58 (1H, d, IndCHH, J 1.2
Hz), 3.50 (1H, d, CHHO, J ) 9.2 Hz), 4.08 (1H, d, CHHO, J )
9.2 Hz), 5.00 (1H, dq, CHCH3, J ) 6.8, 6.8 Hz), 5.18 (2H, dd,
CH2O, J ) 13.2, 18.4 Hz), 6.74 (1H, s, arom), 6.74 (1H, d, arom,
J ) 7.2 H), 6.76 (1H, d, arom, J ) 2.4 Hz), 7.03 (1H, dt, arom,
J ) 0.4, 7.2 Hz), 7.14 (1H, t, arom, J ) 7.2 Hz), 7.22-7.33
(8H, m, arom), 7.47 (1H, d, arom, J ) 8.4 Hz), 7.56 (2H, d,
arom, J ) 6.8 Hz), 7.75 (1H, s, NH); νmax 3337, 1713, 1661,
1494, 1455, 1246, 1065, 743 cm-1; HRMS for C31H32N3O5
(13) Cativiela, C.; D´ıaz-de-Villegas, M. D. Stereoselective Synthesis
of Quaternary R-Amino Acids. Part 1: Acyclic Compounds.
Tetrahedron Asymm. 1998, 9, 3517-3599.
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Heterocyclic Intermediates, XXIV. Enantioselective Synthesis
of (R)-R-Methyltryptophan Methyl Ester and D-Tryptophan
Methyl Ester by the Bislactam Ether Route. Liebigs Ann. Chem.
1985, 413-417.
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5720.
(16) Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J . A. A New
Approach to the Asymmetric Synthesis of R-Methyltryptophan.
Synlett 1994, 302-304.
(17) Anantharamaiah, G. M.; Roeske, R. W. Resolution of R-Methyl
Amino Esters by Chymotrypsin. Tetrahedron Lett. 1982, 23,
3335-3336.
(18) Yee, C.; Blythe, T. A.; McNabb, T. J .; Walts, A. E. Biocatalytic
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tiospecific Synthesis with Amino Acids. Part 1. Tryptophan as
20
requires 526.2342, found 526.2342 (MH+); [R]D -33.4° (c )
0.47, MeOH). Anal. (C31H31N3O5‚0.2 H2O) C, H, N.
[(S)-1-Dim eth yla m in om eth yl-2-(1H-in d ol-3-yl)-1-((S)-1-
p h en yl-eth ylca r ba m oyl)-eth yl]-ca r ba m ic Acid Ben zofu -
r a n -2-ylm eth yl Ester (11e). Procedure as for the preparation
of compound 11b to give a white foam (28 mg, 20%): mp 55-

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