Asymmetric synthesis of β2-tryptophan analogues via Friedel-Crafts alkylation of indoles with a chiral nitroacrylate

Article abstract of DOI:10.1021/jo200733t

The asymmetric Friedel-Crafts alkylation of various indoles with a chiral nitroacrylate provides optically active β-tryptophan analogues after reduction of the nitro group and removal of the chiral auxiliary. This reaction generally occurs in good yield a

Full text of DOI:10.1021/jo200733t

ARTICLE
pubs.acs.org/joc
Asymmetric Synthesis of β2-Tryptophan Analogues via FriedelꢀCrafts
Alkylation of Indoles with a Chiral Nitroacrylate
Nikola Pavlov,†,‡ Pierre Gilles,† Claude Didierjean,§ Emmanuel Wenger,§ Emilia Naydenova,‡
Jean Martinez,† and Monique Calmꢀes*,†
†Institut des Biomolꢁecules Max Mousseron (IBMM) UMR 5247 CNRS-Universitꢁe Montpellier 1 et Universitꢁe Montpellier 2,
B^atiment Chimie (17), Universitꢁe Montpellier 2, place E. Bataillon, 34095 Montpellier cedex 5, France
‡Department of Organic Chemistry, University of Chemical Technology and Metallurgy, 8 Kliment Ohridski blvd., Sofia 1756, Bulgaria
§Laboratoire de Crystallographie, Rꢁesonance Magnꢁetique et Modꢁelisation, Nancy Universitꢁe, UMR7036 CNRS-UHP,
Boulevard des Aiguillettes, BPP239, 54506 Vandoeuvre-Lꢀes-Nancy Cedex, France
S Supporting Information
b
ABSTRACT: The asymmetric FriedelꢀCrafts alkylation of various indoles with a
chiral nitroacrylate provides optically active β-tryptophan analogues after reduction
of the nitro group and removal of the chiral auxiliary. This reaction generally occurs
in good yield and high diastereoselectivity (up to 90:10).
’ INTRODUCTION
biologically active materials with enhanced resistance to enzy-
matic degradation6 and relevant roles in medicinal chemistry.7
Herein, we report the preparation of enantiopure β-tryptophan
analogues 5, for which only very few asymmetric synthesis have
been reported.
The enantioselective preparation of the two β-homologues of
tryptophan, i.e., N-Fmoc-(or N-Z)-3-amino-4-(N-Boc-1H-indol-
3-yl)butanoic acid 3 (β3-homotryptophan) and N-Boc-3-amino-
2-(1H-indol-3-yl)methyl propionic acid 4 (β2-homotryptophan)
have been previously described via Curtius degradation of a
succinic acid derivative and aminomethylation of chiral silyl enol
ethers, respectively.8
Tryptophan 1, an essential amino acid, both functions as a
building block in protein biosynthesis and as a biochemical
precursor. It is abundantly found in most biologically active
peptides that exhibit various physiological properties, in parti-
cular hormonal and antimicrobial activities.1 Some of its natural
derivatives such as serotonin and tryptamine, and also unnatural
derivatives such as sumatriptan, have neurophysiologic effects.2
Tryptophan analogues are also important building blocks for the
synthesis of peptidomimetics, natural products, and biologically
active compounds.3 Another important property of tryptophan
and tryptophan analogues is related to the fluorescence of the
indole ring that can be used to study conformational changes in
protein and in proteinꢀmembrane interactions.4
Concerning β-tryptophan analogues 5, the racemic 5-methoxy
analogue (R1 = R3= H and R2 = 5-OCH3) presents antihyperten-
sive activity9 and has previously been obtained from the corre-
sponding 3-indolylacetonitrile. More recently, the FriedelꢀCrafts
alkylation of various indoles with the (E)-methyl-3-nitroacrylate
has been developed to provide racemic nitro precursors 6 of
In view of the central role that tryptophan plays particularly in
peptides and proteins, the preparation of new analogues in an
enantiomericallypure form is particularly attractive. In connection
with a project exploiting the use of the new chiral β-nitroacrylate
(R)-25 in organic synthesis, we have focused our attention to the
development of enantiopure β-amino acids synthesis. These
derivatives incorporated into peptides and proteins will result in
Received: April 19, 2011
Published: June 14, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200733t J. Org. Chem. 2011, 76, 6116–6124
|

The Journal of Organic Chemistry
ARTICLE
β-tryptophan derivatives 5.10 The preparation of optically active
compounds via ring-opening of chiral methyl N-Z-2-aziridine
carboxylate with indoles has been reported11 to afford a mixture
of optically active β-tryptophan methyl esters analogues 7 and
the corresponding R-regioisomers 8. These two series of com-
pounds were separated by repeated column chromatography.
Finally, the (R)-di-N-Z protected tryptophan analogue 5 (R1 =
R3 = Z and R2 = H) is also obtained, after removal of the chiral
auxiliary, using an electrophilic attack of the aminomethyl cation
[H2NCH2]+ on the chiral enolate derived from the chiral 3-acyl-
1,3-oxazolidin-2-one 9.12
Scheme 1. Asymmetric FriedelꢀCrafts Alkylation of Indoles
10aꢀf with the β-Nitroacrylate (R)-2
Table 1. Solvent and Temperature Effects on the Friedelꢀ
Crafts Reaction of N-Me Indole 10a with β-Nitroacrylate (R)-2
time conversion (30R,2S)/(30R,2R)
entry
solventa
CH2Cl2
temp
(h)
(%)b
11aꢀf (%)d
1
2
3
4
5
6
r.t.
r.t.
r.t.
16
16
16
16
42
>99
>99
>99c
>99
>99
98
88/12
88/12
91/9
toluene
THF
e
c
Et2O/CH2Cl2 r.t.
/
CH2Cl2
CH2Cl2
ꢀ20 °C
90/10
91/9
The FriedelꢀCrafts alkylation between an aromatic C-nucleo-
phile and an electron-deficient olefin is a powerful method for
carbonꢀcarbon bond formation. The FriedelꢀCrafts reactivity of
indoles, that are electron-rich heteroaromatic and efficient Michael
acceptors, has been extensively studied under Lewis acid catalysis.
In the case of tryptophan analogues, the asymmetric version of this
reaction has only been developed usingreactionof an indole with a
glyoxylimine to yield optically active R-(3-indolyl)glycine.13
The FriedelꢀCrafts alkylation of indoles with a chiral β-nitro-
acrylate is an attractive reaction to provide optically active
β-tryptophan analogues 5, because the nitro functional group is a
strongly electron-withdrawing group that can be readily trans-
formed into an amino functional group. We present herein our
results concerning the asymmetric FriedelꢀCrafts alkylation of
substituted indoles with the β-nitroacrylate (R)-2, and the
following transformations were performed to afford optically
active β-tryptophan analogues 5.
ꢀ78 °C and 96
ꢀ40 °Cf
a 0.15 M nitroacrylate concentration. b Determined by HPLC analysis of
the crude product and based on nitroacrylate disappearance. c Side
products formed. d Determined by HPLC (achiral and chiral columns),
LC/MS, and 1H NMR analysis. e 10% of CH2Cl2 was added to solubilize
f
totally the nitroacrylate. After 24 h, the temperature was increased
to ꢀ40 °C.
temperature, dichloromethane and toluene as solvents yielded
similar results in both reaction rate and stereoselectivity (Table 1,
entry 2). When the reaction was carried out in a more polar
solvent such as tetrahydrofuran, a minor effect on diastereos-
electivity was detected (Table 1, entry 3). However, HPLC
analysis of the crude reaction revealed formation of side pro-
ducts, which is also the case when a mixture of diethyl ether and
dichloromethane was used (Table 1, entry 4). We also observed
that an increase of the concentration of the reaction mixture, i.e.,
0.35 M instead of 0.15 M, had no beneficial effect on the
diastereoselectivity of the FriedelꢀCrafts alkylation and was
associated to the formation of side products.15 In addition, when
the reaction was carried out at lower temperature (ꢀ20 °C), we
observed an enhanced selectivity of the FriedelꢀCrafts alkylation
but a decrease of the reaction rate15 (Table 1, entry 5). At
ꢀ78 °C, only 11% of the nitroacrylate (R)-2 was transformed
after 24 h. On the other hand, increasing the temperature to
ꢀ40 °C allowed a total conversion of β-nitroacrylate (R)-2
within 96 h to yield a 91/9 mixture of the two diastereoisomers
11a. This slight improvement to the stereoselectivity was not
attractive enough, considering the increase in the reaction time.
We chose to perform the alkylation reactions in dichloro-
methane, at room temperature for the following syntheses.
To select the Lewis acid, which is assumed to form a 1,3-metal
bonding species with the nitro functional group during Friedelꢀ
Crafts alkylation of nitroalkenes,10,16 we evaluated other metal
and lanthanide triflates.
’ RESULTS AND DISCUSSION
The FriedelꢀCrafts alkylation of β-nitroacrylate (R)-2 with N-
methylindole 10a (R1 = CH3 and R2 = H), used as representative
indole, was first carried out according to the protocol described by
Chen et al.,10 i.e., room temperature using copper(II) triflate,
Cu(OTf)2 (5 mol %) as Lewis acid (Scheme 1). We used dry
dichloromethane as solvent because of the low solubility of the β-
nitroacrylate (R)-2 in diethyl ether. Under these conditions, a
total conversion of the β-nitroacrylate (R)-2 was observed within
16 h to yield the alkylated product 11a. Analysis of the crude
reaction by HPLC (achiral and chiral columns), LC/MS, and 1H
NMR showed the formation of a mixture of two diastereoisomers
11a, one being predominant (88/12 ratio) (Table 1, entry 1).14
In an attempt to increase the stereoselectivity of the reaction,
we investigated several reaction parameters including solvents,
Lewis acid, temperatures, and concentration of reactants. Solvent
and temperature effects are summarized in Table 1. Using
Cu(OTf)2 as additive and performing the reaction at room
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The Journal of Organic Chemistry
ARTICLE
No improvement was observed using lanthanide complexes
Yb(OTf)3 and Er(OTf)3 (Table 2, entries 4 and 5). On the other
hand, Zn(OTf)2 gave fast reaction at room temperature, how-
ever, with lower selectivity (Table 2, entries 2 and 3). A better
selectivity was obtained using Zn(OTf)2 at lower temperature
(ꢀ20 °C) but not higher than that obtained when using Cu-
(OTf)2, Yb(OTf)3, or Er(OTf)3 at room temperature (Table 2,
entries 3, 1, 4, and 5). In the absence of Lewis acid the reaction
proceeded rapidly with a small decrease of the selectivity
compared to reactions carry out with Cu(OTf)2, Yb(OTf)3, or
Er(OTf)3, (Table 2, entry 6).17 However, in the absence of Lewis
acid, the reaction became too slow when the reaction tempera-
ture was lowered to ꢀ40 °C (Table 2, entry 7) and showed a
slight decrease of the reaction rate without increase of the selec-
tivity from room temperature to 0 °C (Table 2, entry 8).
Encouraged by the results obtained with the N-methylindole,
the FriedelꢀCrafts alkylation of a variety of indoles 10bꢀf with
the β-nitroacrylate (R)-2 was investigated using the optimized
conditions and results are summarized in Table 3.
All indole derivatives tested in these conditions, i.e., Cu(OTf)2
as additive at room temperature and in dichloromethane, pro-
vided the corresponding alkylated products in moderate to good
yields depending on the reaction time and on the nature of the
substituent on the nitrogen or on the 5/6-position of the indole
ring (Table 3). The N-methylindole 10a and the unprotected
indole 10b gave total conversion of the nitroacrylate within 16
and 22 h, respectively (Table 3, entries 1 and 2). A similar result
was obtained in the presence of the electron-donating group
5-OCH3 (Table 3, entry 3). With fluoro and bromo functional
groups that have opposite inductive (ꢀI) and mesomeric (+M)
effects, the mesomeric effect could be considered as the most
significant because the corresponding expected products were
obtained in fairly good yield by extending the reaction time
(Table 3, entries 4 and 5). However, it should be underscored
that in these last cases, byproduct formation (3ꢀ5%)15 related to
the loss of the nitro group appeared after 96 h reaction. On the
other hand, neither electron-donating groups, nor electron-
withdrawing groups, affected significantly the reaction diaster-
eoselectivity. In the presence of the CN electron-withdrawing
group, a significant increase in the reaction time was observed
and only a modest conversion was obtained even after 170 h
(Table 3, entry 4).
In all cases, the main alkylated products 11aꢀe could be
isolated in enantiopure form after column chromatography on
silica gel.18 The absolute configuration of the newly generated
center was assigned by X-ray diffraction analysis of the main
nitroester 11e, after recrystallization from a mixture of diethyl
ether/CH2Cl2/cyclohexane (see Supporting Information). From
the known R configuration of the chiral auxiliary, it was ascer-
tained that compound 11e had the (30R,2S) configuration.
Absolute configurations (30R,2S) of the other main nitroesters
11aꢀd were assigned by analogy with 11e.
On the basis of the diastereofacial selectivity observed in the
presenceor inabsence oftheLewis acid, a plausible stereochemical
model for this asymmetric FriedelꢀCrafts alkylation of indoles is
represented in Figure 1. In this model, the nitroacrylate and the
five-membered ring of the chiral auxiliary are in two perpendicular
planes. The two carbonyl groups are also nearly perpendicular to
each other,19 and the geminal dimethyl groups of the auxiliary,
situated on both sides of the five-membered ring, create minimal
steric interactions while blocking the nitroacrylate re face. To
avoid steric repulsion with the chiral auxiliary, indoles attack
Table 2. Lewis Acid Effects in the FriedelꢀCrafts Reaction of
N-Me Indole 10a with β-Nitroacrylate (R)-2
Lewis
acida
time
t (h)
conversion
(%)b
(30R,2S)/(30R,2R)
11aꢀf (%)d
entry
temp
1
2
3
4
5
6
7
8
Cu(OTf)2 r.t.
Zn(OTf)2 r.t.
16
4
>99
>99
90
88/12
73/27
80/20c
88/12
88/12
84/16
88/12
84/16
Zn(OTf)2 ꢀ20 °C 16
Yb(OTf)3 r.t.
16
16
5
>99
>99
>99
81
Er(OTf)3
r.t.
r.t.
ꢀ
ꢀ
ꢀ
ꢀ40 °C 75 h
0 °C 12
>99
a Solvent = CH2Cl2, 0.15 M nitroacrylate concentration. b Determined
by HPLC analysis of the crude product and based on nitroacrylate
disappearance. c Side products formed. d Determined by HPLC (achiral
and chiral columns), LC/MS, and 1H NMR analysis.
Figure 1. Model for stereocontrol.
Table 3. FriedelꢀCrafts Alkylation of Substituted Indoles 10aꢀf with β-Nitroacrylate (R)-2
entry
indoles
R1
R2
time (h)
conversion (%)a
(30R,2S)/(30R,2R) 11aꢀf (%)b
(30R,2S)-11aꢀf Yieldc/eeb (%)
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
CH3
H
H
H
16
22
22
96
96
170
>99
>99
>99
92
88/12
82/18
86/14
89/11
83/17
ꢀ
36/>99
34/>99
35/>99
30/>99
30/>99
ꢀ
H
5-OCH3
6-F
H
H
5-Br
95
H
5-CN
62
a Determined by HPLC analysis of the crude product and based on nitroacrylate disappearance. b Determined by HPLC (achiral and chiral columns),
LC/MS, and 1H NMR analysis. c Isolated yield.
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ARTICLE
Scheme 2. Transformation of Enantiopure Alkylated Products 11aꢀd into N-Fmoc β-Tryptophan Analogues 13aꢀd
Scheme 3. Optimized Conditions to Transform Enantiopure Alkylated Products 11aꢀd into N-Fmoc β-Tryptophan Analogues
13aꢀd
preferentially from the sterically nonblocked bottom face (si face)
of the double bond to give corresponding (30R,2S) compounds.
The first step to transform the enantiopure alkylated products
11aꢀd into the N-Fmoc β-tryptophan analogues 13aꢀd was the
hydrogenation of the nitro group concomitant with hydrogeno-
lysis of the benzyl ester, in acetic acid and in the presence of 5% of
water, using palladium on charcoal as catalyst. In the absence of
water and/or using a different solvent, no reduction of the nitro
group occurred. The resulting amino esters 12aꢀd were used
without further purification20 and engaged in the LiOH hydrolysis.21
Then Fmoc protection of the amino group using Fmoc-OSu
yielded the corresponding N-Fmoc-(S)-β-tryptophan analogue
(S)-13aꢀd (Scheme 2).
during basic hydrolysis due to the acidity of the proton R to the
amino acid’s ester group of the intermediates 12aꢀd and 14e.
To avoid or to minimize the epimerization, we decided to use
trimethyltin hydroxide reported to suppress undesired epimeriza-
tion during the hydrolysis of an ester bond.22 Furthermore, as the
Fmoc protecting group should remain intact throughout this
hydrolysis, we applied the Me3SnOH conditions to the N-Fmoc
protected substrates 15aꢀd. Application of this new procedure
(Scheme 3) yielded the desired N-(S)-Fmoc-β-tryptophan ana-
logues (S)-13aꢀd ingoodyields withoutundesired epimerization.
’ CONCLUSION
We have established a new route to prepare enantiopure
β-tryptophan analogues ((S)-2-indolyl-β-alanines). We showed
that β-nitroacrylate (R)-2 is a good chiral auxiliary for asym-
metric FriedelꢀCrafts alkylation of indoles. (R)-2-Indolyl-β-
alanines were obtained by the same synthetic route by using
the chiral compound (S)-2. β-Tryptophan analogues are delivered
in their N-Fmoc-protected form, ready to use for instance in
solid-phase peptide synthesis, which is one of the most popular
methods for peptide synthesis. This study provides a new
example of asymmetric β2-tryptophan analogues preparation,
and further studies concerning their applications in medicinal
chemistry and in organic synthesis are now in progress.
In the case of compound 11e, reduction of the nitro group was
performed using Zn/HCl to avoid debromination of the indole
ring observed when using Pd/C as catalyst during the hydrogena-
tion reaction. Under this condition, the benzyl ester of the chiral
auxiliary was preserved and the compound 14e was obtained.
LiOH cleavage and Fmoc protection provided the N-Fmoc-(S)-
β-tryptophan analogue (S)-13e.
To control the optical purity of compounds 13aꢀe and/or to
detect the possible epimerization that could have occurred
during the removal of the chiral auxiliary, we performed Friedelꢀ
Crafts reactions with racemic nitroacrylate (RS)-2. These experi-
ments led to the corresponding racemic N-Fmoc-β-tryptophan
analogues rac-13aꢀe, after transformation of the different race-
mic esters rac-11aꢀe. The HPLC profile of each racemic mixture
rac-13aꢀe was then compared to the compounds obtained from
the chiral experiments. We found that transformation of enan-
tiopure alkylated products 11aꢀe took place with a low but
significant degree of epimerization (10ꢀ12%) that may occur
’ EXPERIMENTAL SECTION
General Remarks. All reagents were used as purchased from
commercial suppliers without further purification. Solvents were dried
1
and purified by conventional methods prior to use. H or 13C NMR
spectra (DEPT, 1H/13C 2D-correlations) were recorded using the
6119
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The Journal of Organic Chemistry
ARTICLE
solvent as internal reference. Data are reported as follows: chemical
shifts (δ) in parts per million, coupling constants (J) in hertz (Hz). The
ESI mass spectra were recorded with a platform II quadrupole mass
spectrometer fitted with an electrospray source. HPLC analyses were
performed with variable detector using: column A: SymmetryShield
RP-18, 3.5 μm, (50 ꢁ 4.6 mm), flow: 1 mL/min, H2O (0.1% TFA)/
CH3CN (0.1% TFA), gradient 0f100% (15 min) and 100% (4 min);
column B: Chromolith SpeedROD RP-18e, 2 μm, (50 ꢁ 4.6 mm), flow:
3 mL/min, H2O (0.1% TFA)/CH3CN (0.1% TFA), eluent I: gradient
0f100% (4 min) and 100% (1 min), eluent II: gradient 0f100% (10 min)
and 100% (1 min); column C: Chiracel OD-R, flow: 1 mL/min, H2O
(0.1% TFA)/CH3CN (0.1% TFA), eluent I: 20/80; eluent II: 40/60;
eluent III: 30/70, eluent IV: 0/100; column D: Chiracel OJ-R, flow:
1 mL/min, H2O (0.1% TFA)/CH3CN (0.1% TFA); eluent I: 40/60;
HRMS were recorded in positive mode using NBA (3-nitrobenzyl alcohol
or GT (glycerol/thioglycerol) as matrix. An automated flash purification
system was often used for the flash chromatography on silica gel.23
(R)-Benzyl 4-(3-(3-Nitroacryloyloxy)-4,4-dimethyl-2-oxo-
pyrrolidin-1-yl)benzoate (R)-2. The enantiopure nitroacrylate (R)-
2 was prepared as previously described5 except for the last step that has
been optimized. Mesyl chloride (1.04 mL, 13.15 mmol, 3 equiv) was
added dropwise at ꢀ78 °C and under argon to a stirred solution of
compound (3S,20RS)-benzyl 4-(3-(2-hydroxy-3-nitropropionyloxy)-4,4-
dimethyl-2-oxopyrrolidin-1-yl)benzoate (2.00 g, 4.38 mmol, 1 equiv) in dry
CH2Cl2 (25 mL). Then NEt3 (2.44 mL, 17.52 mmol, 4 equiv) was added
under stirring, and the reaction mixture was immediately diluted with
dichloromethane (80 mL). This organic layer was successively washed with
a 0.1 N HCl solution (40 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude nitroacrylate (R)-2 (quantitative yield)
was used without further purification in the following step. HPLC, MS, and
1H and 13C NMR data are identical to those previously described.5
General Procedure for Asymmetric FriedelꢀCrafts Alkyla-
tions of Indoles with β-Nitroacrylate (R)-2. To a solution of
β-nitroacrylate (R)-2 (1.0 g, 2.28 mmol, 1 equiv) in dry CH2Cl2
(16 mL) under argon atmosphere was added Cu(OTf)2 (40 mg, 0.16 mmol,
0.05 equiv). The solution was stirred at room temperature for 5 min, and
indole 10 (1.2 equiv) was added. After 16ꢀ96 h stirring at the same
temperature, the nitroacrylate 2 was consumed (monitored by HPLC
column B). The solvent was removed under reduced pressure, and the
residue was purified by automated flash chromatography on silica gel.23
(30R,2S)-[N-(4-Benzyloxycarbonylphenyl)-4,4-dimethyl-2-
oxopyrrolidin-3-yl] 2-(1-Methyl-1H-indol-3-yl)-3-nitropropio-
nate (30R,2S)-11a. Synthesized according to the general procedure
from N-methylindole 10a (358 mg, 2.74 mmol, 1.2 equiv) at room
temperature for 16 h. The crude expected product 11a (>99% yield)
was obtained as a brown oil. The expected pure nitro ester (30R,2S)-11a
(467 mg, 0.82 mmol, 36% yield, 99% ee) was obtained as an off-white
solid after automated flash column chromatography on silica gel (car-
tridge 100 g) using a 40/60 isocratic elution of a binary system of cyclo-
118.7, 119.1, 120.0, 122.4, 126.2, 128.2, 128.3, 128.6, 130.8 (CH-aromand
CH-indole), 136.0, 137.1, 142.9 (C-arom), 165.8, 168.7, 171.0 (CdO);
HRMS (ESI) Calcd for C32H32N3O7 (MH+) 570.2240, found 570.2250.
(30R,2S)-[N-(4-Benzyloxycarbonylphenyl)-4,4-dimethyl-
2-oxopyrrolidin-3-yl] 2-(1H-Indol-3-yl)-3-nitropropionate
(30R,2S)-11b. Synthesized according to the general procedure from in-
dole 10b (320 mg, 2.74 mmol, 1.2 equiv) at room temperature for 22 h.
The crude expected product 11b (>99% yield) was obtained as a brown
oil. The expected pure nitro ester (30R,2S)-11b (430 mg, 0.77 mmol,
34% yield, 98% ee) was obtained as an off-white solid after automated
flash column chromatography on silica gel (cartridge 100 g) using a
10ꢀ40% linear gradient elution (12 CV)23 followed by a 40/60 isocratic
elution (8 CV)23 of a binary system of cyclohexane and dichloromethaneꢀ
20
diethyl ether (1.5/2.5). Mp 74ꢀ75 °C; [R]D ꢀ56 (c 1.0, CH2Cl2); tR
(HPLC, column B, eluent I) 2.8 min; tR (HPLC, column C, eluent I)
11.0 min; [tR diastereoisomer (30R,2R) (HPLC, column C, eluent I)
9.9 min]; MS (ESI) m/z: 556.2 [(M + H)+], 578.0 [(M + Na)+]; 1H
NMR (400 MHz, CDCl3) δ (ppm): 1.11 (s, 3H, CH3), 1.27 (s, 3H, CH3),
3.47 (d, J = 9.5 Hz, 1H, 50-H), 3.55 (d, J = 9.5 Hz, 1H, 50-H), 4.63 (dd, J =
3.7 and 14.9 Hz, 1H, HCHNO2), 4.80 (dd, J = 3.7 and 10.6 Hz, 1H,
HCCO-O), 5.09 (dd, J = 10.6 and 14.9 Hz, 1H, HCHNO2), 5.26 (s, 2H,
OCH2C6H5), 5.45 (s, 1H, 30-H), 7.10 (m, 3H, H-arom and H-indole),
7.23ꢀ7.37 (m, 6H, H-arom and H-indole), 7.56 (br t, 3H, H-arom and
H-indole), 7.96 (d, 2H, H-arom); 13C NMR (100 MHz, CDCl3) δ
(ppm):20.1(CH3), 23.6(CH3), 36.4(C-40), 39.7 (CHCO-O), 56.5 (C-50),
65.7 (OCH2C6H5), 74.2 (CH2NO2), 78.0 (C-30), 105.4 (C-indole),
110.8 (CH-indole), 117.0, 117.5, 119.2, 121.7, 122.6 (CH-arom and CH-
indole), 124.6, 125.2 (C-arom), 127.1, 127.2, 127.3, 129.7, (CH-arom
and CH-indole), 135.0, 135.2, 141.8 (C-arom), 164.7, 167.8, 170.0
(CdO); HRMS (ESI) Calcd for C31H30N3O7 (MH+) 556.2084, found
556.2089.
(30R,2S)-[N-(4-Benzyloxycarbonylphenyl)-4,4-dimethyl-2-
oxopyrrolidin-3-yl] 2-(5-Methoxy-1H-indol-3-yl)-3-nitropro-
pionate (30R,2S)-11c. Synthesized according to the general procedure
from 5-methoxyindole 10c (403 mg, 2.74 mmol, 1.2 equiv) at room tem-
perature for 22 h. The crude expected product 11c (>99% yield) was
obtained as a brown oil. The expected pure nitro ester (30R,2S)-11c
(467 mg, 0.79 mmol, 35% yield, 98% ee) was obtained as an off-white
solid after automated flash column chromatography on silica gel (car-
tridge 100 g) using a 10ꢀ40% linear gradient elution (12 CV)23 followed
by a 40/60 isocratic elution (12 CV)23 of a binary system of cyclohexane
20
and dichloromethaneꢀdiethyl ether (1.5/2.5). Mp 66ꢀ67 °C; [R]D
ꢀ68 (c 1.0, CH2Cl2); tR (HPLC, column B, eluent I) 2.7 min; tR (HPLC,
column C, eluent II) 36.9 min; [tR diastereoisomer (30R,2R) (HPLC,
column C, eluent II) 34.5 min]; MS (ESI) m/z: 586.2 [(M + H)+]; 1H
NMR (400 MHz, CDCl3) δ (ppm): 1.12 (s, 3H, CH3), 1.28 (s, 3H,
CH3), 3.48 (d, J = 9.6 Hz, 1H, 50-H), 3.55 (d, J = 9.6 Hz, 1H, 50-H), 4.62
(dd, J = 3.9 and 14.9 Hz, 1H, HCHNO2), 4.75 (dd, J = 3.9 and 10.6 Hz,
1H, HCCO-O), 5.08 (dd, J = 10.6 and 14.9 Hz, 1H, HCHNO2), 5.27
(s, 2H, OCH2C6H5), 5.45 (s, 1H, 30-H), 6.78 (dd, J = 2.3 and 8.8 Hz, 1H,
H-indole), 6.96 (d, J = 2.3 Hz, 1H, H-indole), 7.07 (br s, 1H, H-indole),
7.14 (d, J = 8.8 Hz, 1H, H-indole), 7.26ꢀ7.36 (m, 5H, H-arom), 7.56
(d, J = 7.0 Hz, 2H, H-arom), 7.97 (d, J = 7.0 Hz, 2H, H-arom),
8.32 (br s, 1H, NH); 13C NMR (100 MHz, CDCl3) δ (ppm): 21.1
(CH3), 24.6 (CH3), 37.4 (C-40), 40.7 (CHCO-O), 55.9 (OCH3), 57.5
(C-50), 66.7 (OCH2C6H5), 75.2 (CH2NO2), 79.0 (C-30), 99.9 (CH-
indole), 106.0 (C-indole), 112.6, 112.9 (CH-indole), 118.7 CH-arom),
124.0 (CH-indole), 126.1, 126.2 (C-arom), 128.2, 128.3, 128.6, 130.8
(CH-arom), 132.4, 136.0, 142.8, 154.5 (C-arom), 165.8, 168.9, 171.0
(CdO); HRMS (ESI) Calcd for C32H32N3O8 (MH+) 586.2189, found
586.2194.
20
hexane and dichloromethaneꢀdiethyl ether (2/3). Mp 67ꢀ68 °C; [R]D
ꢀ47 (c 1.0, CH2Cl2); tR (HPLC, column A) 12.3 min; tR (HPLC,
column C, eluent I) 22.9 min; [tR diastereoisomer (30R,2R) (HPLC,
column C, eluent I) 9.2 min]; MS (ESI) m/z: 570.0 [(M + H)+], 592.0
1
[(M + Na)+]; H NMR (400 MHz, CDCl3) δ (ppm): 1.20 (s, 3H,
CH3), 1.37 (s, 3H, CH3), 3.57 (d, J = 9.6 Hz, 1H, 50-H), 3.64 (d, J =
9.6 Hz, 1H, 50-H), 3.79 (s, 3H, N-CH3), 4.76 (dd, J = 3.9 and 14.8 Hz,
1H, HCH-NO2), 4.90 (dd, J = 3.9 and 10.5 Hz, 1H, HCCO-O), 5.17
(dd, J = 10.5 and 14.8 Hz, 1H, HCH-NO2), 5.37 (s, 2H, OCH2C6H5),
5.52 (s, 1H, 30-H), 7.17 (t and s, J = 7.0 Hz, 2H, H-indole), 7.25ꢀ7.48
(m, 7H, H-arom and H-indole), 7.65 (d, J = 8.0 Hz 1H, H-indole), 7.70
(d, J = 7.0 Hz, 2H, H-arom), 8.08 (d, J = 7.0 Hz, 2H, H-arom); 13C NMR
(100 MHz, CDCl3) δ (ppm): 21.1 (CH3), 24.7 (CH3), 33.0 (N-CH3),
37.4 (C-40), 41.0 (CHCO-O), 57.4 (C-50), 66.7 (OCH2C6H5), 75.4
(CH2NO2), 79.1 (C-30), 105.0 (C-indole), 109.9 (CH-indole), 118.3,
(30R,2S)-[N-(4-Benzyloxycarbonylphenyl)-4,4-dimethyl-2-
oxopyrrolidin-3-yl] 2-(6-Fluoro-1H-indol-3-yl)-3-nitropro-
pionate (30R,2S)-11d. Synthesized according to the general procedure
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ARTICLE
from 6-fluoroindole 10d (370 mg, 2.74 mmol, 1.2 equiv) at room
temperature for 96 h. The crude expected product 11d (>99% yield)
was obtained as a brown oil. The pure nitro ester (30R,2S)-11d (392 mg,
0.68 mmol, 30% yield, 96% ee) was obtained as an off-white solid after
automated flash column chromatography on silica gel (cartridge 100 g)
using a 12ꢀ50% linear gradient elution (11 CV)23 followed by a 50/50
isocratic elution (6 CV)23 of a binary system of cyclohexane and dichloro-
0.9 mmol, 3 equiv)21 in water (1 mL) dropwise. The mixture was stirred
at room temperature until completion of the hydrolysis (∼2 h)
(monitored by HPLC, column B). The organic solvent was removed
in vacuo. The aqueous phase was acidified (pH 2), washed with ethyl
acetate (3 ꢁ 10 mL), and concentrated in vacuo. To the residue
dissolved in a mixture of water and acetone (1/1) (20 mL) was added
50 mg (0.6 mmol, 2 equiv) of sodium bicarbonate followed by 101 mg
(0.3 mmol, 1 equiv) of 9-fluorenylmethyloxycarbonyl-N-hydroxysucci-
nimide (Fmoc-OSu). After 2 h of stirring at room temperature, the
organic solvent was removed in vacuo and the aqueous phase was
acidified to pH 2ꢀ3 with 1 N HCl. The aqueous phase was extracted
with ethyl acetate (3 ꢁ 10 mL), and the combined organic extracts were
concentrated in vacuo. The residue was purified by automated flash
column chromatography on silica gel to yield the expected compound
N-Fmoc-(S)-β-tryptophan analogue 13.
Procedure B (Scheme 3). To compound 12 dissolved in a mixture of
water and acetone (1/1) (30 mL) was added sodiumbicarbonate (101 mg,
1.2 mmol, 4 equiv) followed by 9-fluorenylmethyloxycarbonyl-N-hydro-
xysuccinimide (Fmoc-OSu) (189 mg, 0.3 mmol, 1 equiv). After 2 h of
stirring at room temperature (monitored by HPLC, column B), the
organic solvent was removed in vacuo and the aqueous phase was
acidified to pH 2ꢀ3 with 1 N HCl. The aqueous phase was extracted
with ethyl acetate (3 ꢁ 10 mL), and the combined organic extracts were
concentrated in vacuo to yield the crude N-Fmoc-β-tryptophan ester 15,
which was subjected to automated flash column chromatography on
silica gel. A mixture of the purified compound 15 dissolved in 1,2-di-
chloroethane and trimethyltin hydroxide (10 equiv) in a thick-glass tube
with a septum was heated at 80ꢀ85 °C (bath temperature 90ꢀ95 °C),
until completion of the reaction (monitored by HPLC, column B).
Then, the organic solvent was removed in vacuo, and the residue was
dissolved in ethyl acetate. The organic layer was washed with 5% HCl,
brine, and dried over sodium sulfate. The oily product obtained after
removal of the solvent in vacuo was purified by automated flash column
chromatography on silica gel to yield the expected pure N-Fmoc-(S)-
β-tryptophan analogue 13.
(S)-3-(9-Fluorenylmethoxycarbonylamino)-2-(1-methyl-
1H-indol-3-yl)propionic Acid (S)-13a. Synthesized according to
procedure B from compound 11a (170 mg, 0.30 mmol). The crude ex-
pected intermediate acetic acid salt of [N-(4-carboxyphenyl)-4,4-di-
methyl-2-oxopyrrolidin-3-yl] 2-(1-methyl-1H-indol-3-yl)-3-aminopro-
pionate (30R,2S)-12a was first obtained as a brown solid (>99% yield);
tR (HPLC, column B, eluent I) 1.74 min; MS (ESI) m/z: 450.2 [(M +
H)+]. After N-Fmoc protection, the pure N-Fmoc-β-tryptophan ester
(30R,2S)-15a (94 mg, 0.14 mmol, 45% yield) was isolated as a white solid
afterautomatedflash column chromatography on silica gel(cartridge 25 g)
using a 11ꢀ45% linear gradient elution (10 CV)23 followed by a 55/45
isocratic elution (8 CV)23 of a binary system of cyclohexane and
ethylacetate. Mp 121ꢀ122 °C; [R]D20 +71 (c 1.5, CH2Cl2); tR (HPLC,
column B, eluent I) 2.8 min; 99% ee: tR (HPLC, column C, eluent I)
26.9 min; [tR enantiomer (30R,2R) (HPLC, column C) 39.3 min]; MS
(ESI) m/z: 672.2 [(M + H)+], 694.0 [(M + Na)+]; 1H NMR (400 MHz,
CD3COCD3) δ (ppm): 1.16 (s, 3H, CH3), 1.30 (s, 3H, CH3),
3.72ꢀ3.89 (m+s, 7H, 50-CH2, N-CH3 and CH2NH), 4.26 (m, 1H,
OCH2CH), 4.35 (m, 2H, OCH2), 4.47 (m, 1H, CHCOO), 5.69 (s, 1H,
30-H), 7.09 (m, 2H, NH and HC-indole), 7.22 (m, 1H, HC-indole),
7.31ꢀ7.44 (2 m, 6H, HC-Fmoc and HC-indole), 7.75 (d, J = 8.8 Hz, 2H,
H-arom), 7.80ꢀ7.91 (3 m, 5H, HC-Fmoc and HC-indole), 8.08 (d, J =
8.8 Hz, 2H, H-arom); 13C NMR (100 MHz, CD3COCD3) δ (ppm):
20.1 (CH3), 23.1 (CH3), 31.5 (N-CH3), 36.5 (C-40), 43.0 (CH2NH),
43.5 (CHCOO), 46.7 (OCH2CH), 56.4 (C-50), 65.8 (OCH2), 77.9
(C-30), 108.4 (C-indole or C-Fmoc), 109.0 (CH-indole), 117.9, 118.5,
118.6, 119.4, 121.2, 124.9 (CH-arom, CH-Fmoc and CH-indole), 125.6
(C-indole or C-Fmoc), 126.6, 126.7, 126.8, 127.1, 129.9 (CH-arom, CH-
Fmoc and CH-indole), 136.6, 140.7, 142,9, 143.7 (C-arom, C-indole and
20
methaneꢀdiethyl ether (2/3). Mp 79ꢀ80 °C; [R]D ꢀ48 (c1.0, CH2Cl2);
tR (HPLC, column B, eluent I) 2.8 min; tR (HPLC, column D, eluent I)
14.8 min; [tR diastereoisomer (30R,2R) (HPLC, column D, eluent I)
1
24.6 min]; MS (ESI) m/z: 574.2 [(M + H)+]; H NMR (400 MHz,
CDCl3) δ (ppm): 1.14 (s, 3H, CH3), 1.28 (s, 3H, CH3), 3.48 (d, J =
9.6 Hz, 1H, 50-H), 3.56 (d, J = 9.6 Hz, 1H, 50-H), 4.58 (dd, J = 3.9 and
14.9 Hz, 1H, HCHNO2), 4.73 (dd, J = 3.9 and 10.6 Hz, 1H, HCCO-O),
5.08 (dd, J = 10.6 and 14.9 Hz, 1H, HCHNO2), 5.25 (s, 2H, OCH2C6H5),
5.45 (s, 1H, 30-H), 6.80 (m, 2H, H-indole), 6.95 (br s, 1H, H-indole),
7.23ꢀ7.37 (m, 5H, C6H5), 7.43 (dd, J = 8.8 Hz, 1H, H-indole), 7.54 (d,
J = 8.6 Hz, 2H, C6H4), 7.97 (d, J = 8.6 Hz, 2H, C6H4), 8.63 (br s, 1H,
NH); 13C NMR (100 MHz, CDCl3) δ (ppm): 21.1 (CH3), 24.6 (CH3),
37.5 (C-40), 40.6(CHCO-O), 57.6 (C-50), 66.8 (OCH2C6H5), 75.2
(CH2NO2), 79.1 (C-30), 97.9 and 98.2 (CH-indole), 106.3 (C-indole),
108.9 and 109.1 (CH-indole), 118.6 (CH-arom), 118.8 and 118.9 (CH-
indole), 124.0 (CH-indole), 126.4 (C-arom or C-indole), 128.2, 128.3,
128.6, 130.8 (CH-arom), 135.9, 136.2, 136.4, 142.7, 158.9, 161.26 (C-
arom and C-indole), 165.7, 169.0, 171.0 (CdO); HRMS (ESI) Calcd
for C31H29N3O7 F (MH+) 574.1990, found 574.1991.
(30R,2S)-[N-(4-Benzyloxycarbonylphenyl)-4,4-dimethyl-2-
oxopyrrolidin-3-yl] 2-(5-Bromo-1H-indol-3-yl)-3-nitropro-
pionate (30R,2S)-11e. Synthesized according to the general procedure
from 5-bromoindole 10e (537 mg, 2.74 mmol, 1.2 equiv) at room tempera-
ture for 96 h. The crude expected product 11e (>99% yield) was ob-
tained asabrown oil. The expectedpurenitroester (30R,2S)-11e (434 mg,
0.68 mmol, 30% yield, 99% ee) was obtained as an off-white solid after
automated flash column chromatography on silica gel (cartridge 100 g)
using a 12ꢀ50% linear gradient elution (8.5 CV)23 followed by a 50/50
isocratic elution (7 CV)23 of a binary system of cyclohexane and dichloro-
20
methaneꢀdiethyl ether (2/3). Mp 85ꢀ86 °C; [R]D ꢀ89 (c1.0, CH2Cl2);
tR (HPLC, column B, eluent I) 2.9 min; tR (HPLC, column C, eluent II)
51.3 min; [tR diastereoisomer (30R,2R) (HPLC, column C, eluent II)
54.8 min]; MS (ESI) m/z: 633.9 and 636.1[(M + H)+], 656.1 and 658.0
1
[(M + Na)+]; H NMR (400 MHz, CDCl3) δ (ppm): 1.15 (s, 3H,
CH3), 1.29 (s, 3H, CH3), 3.50 (d, J = 9.6 Hz, 1H, 50-H), 3.58 (d, J =
9.6 Hz, 1H, 50-H), 4.57 (dd, J = 3.9 and 14.9 Hz, 1H, HCHNO2), 4.70
(dd, J = 3.9 and 10.6 Hz, 1H, HCCO-O), 5.08 (dd, J = 10.6 and 14.9 Hz,
1H, HCHNO2), 5.26 (s, 2H, OCH2C6H5), 5.46 (s, 1H, 30-H), 6.94
(s, 1H, H-indole), 7.00 (d, J = 8.6 Hz, 1H, H-indole), 7.13 (d, J = 8.6 Hz,
1H, H-indole), 7.23ꢀ7.35 (m, 5H, H-arom), 7.54 (d, J = 8.6 Hz, 2H,
H-arom), 7.66 (s, 1H, H-indole), 7.95 (d, J = 8.6 Hz, 2H, H-arom), 8.74
(brs, 1H, NH);13C NMR(100 MHz, CDCl3) δ(ppm): 21.2(CH3), 24.6
(CH3), 37.5 (C-40), 40.4 (CHCO-O), 57.6 (C-50), 66.7 (OCH2C6H5),
75.0 (CH2NO2), 79.1 (C-30), 105.6 (C-indole), 113.3 (CH-indole),
118.7 (CH-arom), 122.7, 124.6, 125.5 (CH-indole), 126.4, 127.2 (C-arom),
H-indole), HRMS (ESI) Calcd for C31H29BrN3O7 (MH+) 634.1189,
found 634.1199.
General Procedure To Transform Compounds 11aꢀd into
N-Fmoc-(S)-β-Tryptophan Analogues 13aꢀd. A mixture of
compound 11 (0.3 mmol) and 10% Pd/C (320 mg) in acetic acid
(8 mL) and water (400 μL, 5%) was stirred vigorously under 1 atm of H2
for 16 h at room temperature (monitored by HPLC, column B). The
suspension was filtered through Celite, and the filtrate was concentrated
in vacuo to yield quantitatively the acetic acid salt of the expected
compound 12 (>99% yield) that was used without further purification.20
Procedure A (Scheme 2). To compound 12 dissolved in a mixture of
THF/H2O (1/1) (12 mL) was added a solution of LiOH H2O (47 mg,
3
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The Journal of Organic Chemistry
ARTICLE
C-Fmoc), 155.9, 165.6, 169.4, 171.2 (CdO); HRMS (ESI) Calcd for
C40H38N3O7 (MH+) 672.2710, found 672.2715.
and HC-indole), 7.26 (t, J = 7.9 Hz, 3H, HC-Fmoc and HC-indole), 7.53
(d, J = 7.5 Hz, 2H, HC-Fmoc), 7.60 (d, J = 7.9 Hz, 1H, HC-indole), 7.71
(d, J = 7.5 Hz, 2H, HC-Fmoc), 10.07 (br s, 1H, NH-indole); 13C NMR
(100 MHz, CD3COCD3) δ (ppm): 42.9 (CHCO2H), 43.3 (CH2NH),
47.2 (OCH2CH), 66.1 (OCH2), 110.8 (C-indole or C-Fmoc), 111.4,
118.9, 119.0, 119.9, 121.5, 123.0, 125.3, 127.0, 127.6 (CH-Fmoc and
CH-indole), 136.7, 141.2, 144.2, 144.3 (C-indole and C-Fmoc), 156.4,
173.7 (CdO); HRMS (ESI) Calcd for C26H23N2O4 (MH+) 427.1658,
found 427.1651.
After trimethyltin hydroxide hydrolysis of the purified compound
(30R,2S)-15a, the N-Fmoc-β-tryptophan analogue (S)-13a (41 mg,
0.094 mmol, 67% yield) was isolated as a white solid after column
chromatography on silica gel with cyclohexane/ethyl acetate/CH2Cl2/
20
AcOH(5.5/4/0.5/0.1%). Mp118ꢀ119 °C;[R]D ꢀ46 (c1.0, CH2Cl2);
tR (HPLC, column B, eluent I) 2.5 min; 99% ee: tR (HPLC, column C,
eluent I) 11.1 min; [tR enantiomer (R) (HPLC, column C) 17.4 min];
MS (ESI) m/z: 441.3 [(M + H)+]; 1H NMR (400 MHz, CD3COCD3) δ
(ppm): 3.49 (m, 1H, HCHNH), 3.64 (s and m, 4H, HCHNH and
N-CH3), 4.10 (m, 2H, CHCO2H and OCH2CH), 4.19 (m, 2H, OCH2),
6.52 (br t, 1H, NH), 6.92 (t, J = 7.5Hz, 1H, HC-indole), 7.03 (t, J = 7.5 Hz,
1H, HC-indole), 7.12ꢀ7.27 (2 m, 6H, HC-Fmoc and HC-indole), 7.52
(d, J = 7.5 Hz, 2H, HC-Fmoc), 7.58 (d, J = 7.9 Hz, 1H, HC-indole), 7.70
(d, J = 7.5 Hz, 2H, HC-Fmoc); 13C NMR (100 MHz, CD3COCD3)
δ (ppm): 31.9 (N-CH3), 42.8 (CHCO2H), 42.4 (CH2NH), 47.2
(OCH2CH), 66.1 (OCH2), 109.5 (CH-indole), 109.8 (C-indole or
C-Fmoc), 118.9, 119.0, 119.9, 121.5, 125.3, 127.0, 127.3, 127.6 (CH-Fmoc
andCH-indole), 137.2, 141.2, 144.2, 144.3(C-indole andC-Fmoc), 156.4,
173.6 (CdO); HRMS (ESI) Calcd for C27H25N2O4 (MH+) 441.1814,
found 441.1796.
(S)-3-(9-Fluorenylmethoxycarbonylamino)-2-(5-methoxy-
1H-indol-3-yl)propionic Acid (S)-13c. Synthesized according to
procedure B from compound 11c (176 mg, 0.3 mmol). The crude
expected intermediate acetic acid salt of [N-(4-carboxyphenyl)-4,4-
dimethyl-2-oxopyrrolidin-3-yl] 2-(5-methoxy-1H-indol-3-yl)-3-amino-
propionate (30R,2S)-12c was obtained as a brown solid (>99% yield); tR
(HPLC, column B, eluent I) 1.62 min; MS (ESI) m/z: 466.3 [(M + H)+].
After N-Fmoc protection, the N-Fmoc-β-tryptophan ester (30R,2S)-15c
(96 mg, 0.14 mmol, 48% yield) was isolated as a white solid after
automated flash column chromatography on silica gel (cartridge 25 g)
using a 12ꢀ50% linear gradient elution (10 CV)23 followed by a 50/50
isocratic elution (12 CV)23 of a binary system of cyclohexane and ethyl-
20
acetate. Mp 139ꢀ140 °C; [R]D ꢀ43 (c1.4, CH2Cl2);tR (HPLC, column
B, eluent I) 2.6 min; 99% ee: tR (HPLC, column C, eluent I) 10.9 min; MS
(ESI) m/z: 688.1 [(M + H)+] 710.2 [(M + Na)+]; 1H NMR (400 MHz,
CD3COCD3) δ (ppm): 1.05 (s, 3H, CH3), 1.15 (s, 3H, CH3), 3.58 (d,
J = 9.6 Hz, 1H, 50-H), 3.72 (m, 6H, 50-CH2, CH2NH and OCH3), 4.11
(m, 1H, OCH2CH), 4.20 (m, 2H, OCH2), 4.29 (m, 1H, CHCOO), 5.54
(s, 1H, 30-H), 6.66 (dd, J = 8.8 and 2.0 Hz, 1H, HC-indole), 6.90 (br t,
1H, NH), 7.16ꢀ7.28 (2 m, 7 H, HC-Fmoc and HC-indole), 7.60 (d, J =
8.8 Hz, 2H, H-arom), 7.29 (m, 4H, HC-Fmoc and HC-indole), 7.92 (d,
J = 8.8 Hz, 2H, H-arom), 9.99 (s, 1H, NH-indole); 13C NMR (100 MHz,
CD3COCD3) δ (ppm): 20.1 (CH3), 23.1 (CH3), 36.5 (C-40), 42.8
(CH2NH), 43.6 (CHCOO), 46.7 (OCH2CH), 54.5 (OCH3), 56.4 (C-
50), 65.8 (OCH2), 77.8 (C-30), 99.92 (CH-indole), 109.0 (C-indole or
C-Fmoc), 111.6, 117.9, 119.4, 123.2, 124.9 (CH-arom, CH-Fmoc and
CH-indole), 125.6, 126.6 (C-indole or C-Fmoc), 126.7, 127.1, 129.9
(CH-arom, CH-Fmoc and CH-indole), 131.2, 140.7, 142,9, 143.7, 153.7
(C-arom, C-indole and C-Fmoc), 155.9, 165.8, 169.6, 171.3 (CdO);
HRMS (ESI) Calcd for C40H38N3O8 (MH+) 688.2659, found 688.2661.
After trimethyltin hydroxide hydrolysis of the purified compound
(30R,2S)-15c, the N-Fmoc-β-tryptophan analogue (S)-13c (30 mg,
0.066 mmol, 47% yield) was isolated as a white solid after column
chromatography on silica gel with cyclohexane/ethyl acetate/CH2Cl2/
(S)-3-(9-Fluorenylmethoxycarbonylamino)-2-(1H-indol-3-yl)-
propionic Acid (S)-13b. Synthesized according to procedure B from
compound 11b (167 mg, 0.3 mmol). The crude expected intermediate
acetic acid salt of [N-(4-carboxyphenyl)-4,4-dimethyl-2-oxopyrrolidin-
3-yl] 2-(1H-indol-3-yl)-3-aminopropionate (30R,2S)-12b was first ob-
tained as a brown solid (>99% yield); tR (HPLC, column B, eluent I)
1.64 min; MS (ESI) m/z: 436.3 [(M + H)+]. Then, after N-Fmoc pro-
tection, the N-Fmoc-β-tryptophan ester (30R,2S)-15b (118 mg, 0.18 mmol,
60% yield) was isolated as a white solid after automated flash column
chromatography on silica gel (cartridge 25 g) using a 12ꢀ50% linear
gradient elution (10 CV)23 followed by a 50/50 isocratic elution
(10 CV)23 of a binary system of cyclohexane and ethyl acetate. Mp
142ꢀ143 °C;[R]D20 +20 (c 1.5, CH2Cl2); tR (HPLC, column B, eluent I)
2.6 min; 99% ee: tR (HPLC, column C, eluent I) 13.5 min; MS (ESI)
1
m/z: 658.2 [(M + H)+] 680.1 [(M + Na)+]; H NMR (400 MHz,
CD3COCD3) δ (ppm): 1.15 (s, 3H, CH3), 1.30 (s, 3H, CH3), 3.73 (d,
J = 9.6 Hz, 1H, 50-H), 3.88 (m, 3H, 50-CH2 and CH2NH), 4.27 (m, 1H,
OCH2CH), 4.36 (m, 2H, OCH2), 4.49 (m, 1H, CHCOO), 5.70 (s, 1H,
30-H), 7.08ꢀ7.18 (m, 3H, NH and HC-indole), 7.33 and 7.44 (2 m, 6H,
HC-Fmoc and HC-indole), 7.75 (d, J = 8.8 Hz, 2H, H-arom), 7.82ꢀ7.91
(m, 5H, HC-Fmoc and HC-indole), 8.07 (d, J = 8.8 Hz, 2H, H-arom),
10.28 (s, 1H, NH-indole); 13C NMR (100 MHz, CD3COCD3) δ
(ppm): 20.1 (CH3), 23.1 (CH3), 36.5 (C-40), 43.0 (CH2NH), 43.7
(CHCOO), 46.7 (OCH2CH), 56.4 (C-50), 65.8 (OCH2), 77.8 (C-30),
109.3 (C-indole or C-Fmoc), 111.0 (CH-indole), 117.9, 118.3, 118.6,
119.4, 121.2, 122.5, 124.9, 125.6, 126.3 (CH-arom, CH-Fmoc and CH-
indole), 125.5, 126.6 (C-indole or C-Fmoc), 127.1, 130.0 (CH-arom,
CH-Fmoc and CH-indole), 140.7, 142,9, 143.7 (C-arom, C-indole and
C-Fmoc), 155.9, 165.7, 169.5, 171.2 (CdO); HRMS (ESI) Calcd for
C39H36N3O7 (MH+) 658.2553, found 658.2554.
20
AcOH (3/5/2/0.1%). Mp 110ꢀ111 °C; [R]D ꢀ7 (c 0.4, CH2Cl2); tR
(HPLC, column B) (eluant I) 2.3 min, (eluant II) 4.5 min; 99% ee: tR
(HPLC, column C, eluent III) 8.2 min; [tR enantiomer R (HPLC,
column C, eluant III) 10.3 min]; MS (ESI) m/z: 457.3 [(M + H)+]; 1H
NMR (400 MHz, CD3COCD3) δ (ppm): 2.90 (br s, 1H, OH), 3.67 (m,
1H, HCHNH), 3.81 (s and m, 4H, OCH3 and HCHNH), 4.24 (m, 2H,
CHCO2H and OCH2CH), 4.34 (d, J = 6.9 Hz, 2H, OCH2), 6.68 (br s,
1H, NH-Fmoc), 6.80 (dd, J = 2.4 and 8.8 Hz, 1H, CH-indole),
7.28ꢀ7.34 (m, 5H, (CH-Fmoc and CH-indole),), 7.41 (t, J = 7.4 Hz,
2H, CH-Fmoc), 7.68 (d, J = 7.5 Hz, 2H, HC-Fmoc), 7.86 (d, J = 7.5 Hz,
2H, HC-Fmoc), 10.08 (br s, 1H, NH-indole); 13C NMR (100 MHz,
CD3COCD3) δ (ppm): 42.9 (CHCO2H), 43.2 (CH2NH), 47.2
(OCH2CH), 54.9 (CH3), 66.1 (OCH2), 100.7 (CH-indole), 110.5
(C-indole or C-Fmoc), 111.8, 112.1, 119.9, 123.4, 123.6, 125.3, 127.0,
127.3, 127.6 (CH-Fmoc and CH-indole), 131.8, 141.2, 144.3, 154.0
(C-indole or C-Fmoc), 156.4, 173.7 (CdO); HRMS (ESI) Calcd for
C27H25N2O5 (MH+) 457.1763, found 457.1774.
After trimethyltin hydroxide hydrolysis of the purified compound
(30R,2S)-15b, the N-Fmoc-β-tryptophan analogue (S)-13b (51 mg,
0.119 mmol, 66% yield) was isolated as a white solid after column
chromatography on silica gel with cyclohexane/ethyl acetate/CH2Cl2/
20
AcOH (3/5/2/0.1%). Mp 129ꢀ130 °C; [R]D ꢀ60 (c 1.0, CH2Cl2);
tR (HPLC, column B) (eluent I) 2.3 min, (eluent II) 4.6 min; 98% ee: tR
(HPLC, column C, eluent III) 11.3 min; [tR enantiomer (R) (HPLC,
column C) 16.6 min]; MS (ESI) m/z: 427.2 [(M + H)+]; 1H NMR (400
MHz, CD3COCD3) δ (ppm): 2.75 (br s, 1H, OH), 3.51 (m, 1H,
HCHNH), 3.66 (m, 1H, HCHNH), 4.08ꢀ4.19 (m, 4H, CHCO2H,
OCH2CH and OCH2), 6.54 (br t, 1H, NH-Fmoc), 6.90 (t, J = 7.4 Hz,
1H HC-indole), 7.00 (t, J=7.1Hz, 1HHC-indole), 7.14 (m, 3H, HC-Fmoc
(S)-3-(9-Fluorenylmethoxycarbonylamino)-2-(6-fluoro-1H-
indol-3-yl)propionic Acid (S)-13d. Synthesized according to the
procedure B from compound 11d (172 mg, 0.3 mmol). The crude
expected intermediate acetic acid salt of [N-(4-carboxyphenyl)-4,
6122
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ARTICLE
4-dimethyl-2-oxopyrrolidin-3-yl] 2-(6-fluoro-1H-indol-3-yl)-3-amino-
propionate (30R,2S)-12d was obtained as a brown solid (>99% yield);
tR (HPLC, column B, eluent I) 1.71 min; MS (ESI) m/z: 454.2 [(M +
H)+]. Then, after N-Fmoc protection, the N-Fmoc-β-tryptophan ester
(30R,2S)-15d (140 mg, 0.21 mmol, 69% yield) was isolated as a white
solid after automated flash column chromatography on silica gel (car-
tridge 25 g) using a 12ꢀ50% linear gradient elution (10 CV)23 followed
by a 50/50 isocratic elution (9 CV)23 of a binary system of cyclohexane
and ethyl acetate. Mp 177 °C; [R]D20 +33 (c 1.5, CH2Cl2); tR (HPLC,
column B, eluent I) 2.7 min; 99% ee: tR (HPLC, column C, eluent I) 11.1
min; MS (ESI) m/z: 676.2 [(M + H)+]; 1H NMR (400 MHz,
CD3COCD3) δ (ppm): 1.15 (s, 3H, CH3), 1.30 (s, 3H, CH3), 3.73
(d, J = 9.6 Hz, 1H, 50-H), 3.86 (m, 3H, 50-CH2 and CH2NH), 4.26 (m,
1H, OCH2CH), 4.37 (m, 2H, OCH2), 4.47 (m, 1H, CHCOO), 5.69 (s,
1H, 30-H), 6.92 (dt, J = 9.6 and 2.2 Hz, 1H, HC-indole), 7.06 (br t, 1H,
NH), 7.18 (dd, J = 9.9 and 2.2 Hz, 1H, HC-indole), 7.31ꢀ7.47 (2 m, 5H,
HC-Fmoc and HC-indole), 7.74ꢀ7.90 (m, 6H, H-arom, HC-Fmoc and
HC-indole), 8.07 (d, J = 8.8 Hz, 2H, H-arom), 10.38 (s, 1H, NH-indole);
13C NMR (100 MHz, CD3COCD3) δ (ppm): 20.4 (CH3), 24.4 (CH3),
37.9 (C-40), 44.2 (CH2NH), 47.9 (CHCOO), 48.0 (OCH2CH), 57.8
(C-50), 67.2 (OCH2), 79.2 (C-30), 98.3 and 98.5 (C-indole), 108.6 and
108.4 (CH-indole), 111.2 (C-indole or C-Fmoc), 119.3, 120.8, (CH-
Fmoc and CH-indole), 124.5, 127.0 (C-indole or C-Fmoc), 126.2, 127.9,
128.5, 131.6 (CH-arom, CH-Fmoc and CH-indole), 137.3, 137.6, 142.1,
144.3, 145.1, 157.3, 159.5, 161.9, 167.1, 170.8, 172.5 (C-arom, C-indole
and C-Fmoc, CdO); HRMS (ESI) Calcd for C39H35N3O7 F(MH+)
676.2459, found 676.2453.
automated flash column chromatography on silica gel (cartridge 25 g)
using a 10ꢀ40% linear gradient elution (10 CV)23 followed by a 60/40
isocratic elution (8 CV)23 of a binary system of cyclohexane and ethyl
acetate. Mp 112 °C; [R]D ꢀ21 (c 1.0, CH2Cl2); tR (HPLC, column B,
20
eluent I) 3.2 min; 98% ee: tR (HPLC, column C, eluent IV) 12.5 min;
MS (ESI) m/z: 826.1 and 826.0 [(M + H)+], 848.1 and 850.0 [(M +
Na)+]; 1H NMR (400 MHz, CD3COCD3) δ (ppm): 1.15 (s, 3H, CH3),
1.30 (s, 3H, CH3), 3.72 (d, J = 9.6 Hz, 1H, 50-H), 3.86 (m, 3H, 50-H and
CH2NH), 4.25 (br t, J = 7.2 Hz, 1H, OCH2CH), 4.34 (m, 2H, OCH2),
4.45 (dd, J = 6.4 and 8.8 Hz, 1H, CHCOO), 5.37 (s, 2H, CH2C6H5),
5.68 (s, 1H, 30-H), 7.04 (br t, 1H, NH), 7.25ꢀ7.44 (m, 10H, HC-Fmoc,
H-arom, and HC-indole), 7.51 (br d, J = 7.6 Hz, 2H, HC-Fmoc and/or
HC-indole), 7.73 (d, J = 8.6 Hz, 2H, H-arom), 7.88 (m, 4H, HC-Fmoc
and/or HC-indole), 7.99 (br s, 1H, HC-Fmoc and/or HC-indole), 8.07
(d, J = 8.6 Hz, 2H, H-arom), 10.50 (s, 1H, NH-indole); 13C NMR (100
MHz, CD3COCD3) δ (ppm): 21.5 (CH3), 24.4 (CH3), 37.9 (C-40),
44.3 (CH2NH), 44.8 (CHCOO), 48.1 (OCH2CH), 57.7 (C-50), 67.0
(OCH2), 67.2 (OCH2C6H5), 79.3 (C-30), 110.5, 112.9, 113.0 (C-arom,
C-indole, and/or C-Fmoc), 114.3, 119.3, 120.8, 122.3, 125.8, 126.2,
127.9, 128.5, 128.9, 129.4, 131.2 (CH-arom, CH-Fmoc and CH-indole),
136.28, 137.5, 142.1, 144.5, 145.1 (C-arom, C-indole, andC-Fmoc), 157.3,
166.1, 170.7, 172.4 (CdO); HRMS (ESI) Calcd for C46H41BrN3O7
(MH+) 826.2128, found 826.2114.
After trimethyltin hydroxide hydrolysis of the purified compound
(30R,2S)-16e, the N-Fmoc-β-tryptophan analogue (S)-13e (44 mg,
0.088 mmol, 63% yield) was isolated as a white solid after column
chromatography on silica gel with cyclohexane/ethyl acetate/CH2Cl2/
20
AcOH (3/5/2/0.1%). Mp 107ꢀ108 °C; [R]D ꢀ13 (c 0.4, CH2Cl2);
After trimethyltin hydroxide hydrolysis of the purified compound
(30R,2S)-15d, the N-Fmoc-β-tryptophan analogue (S)-13d (33 mg,
0.075 mmol, 36% yield) was isolated as a white solid after column
chromatography on silica gel with cyclohexane/ethyl acetate/CH2Cl2/
tR (HPLC, column B) (eluant II) 4.8 min; 98% ee: tR (HPLC, column C,
eluent III) 10.9 min; [tR enantiomer R (HPLC, column C, eluant III)
12.6 min]; MS (ESI) m/z: 504.9 and 506.9 [(M + H)+], 526.9 and 528.9
[(M + Na)+]; 1H NMR (400 MHz, CD3COCD3) δ (ppm): 3.64 (m,
1H, HCHNH), 3.81 (m, 1H, HCHNH), 4.08ꢀ4.19 (m, 4H, CHCO2H,
OCH2CH and OCH2), 6.73 (br t, 1H, NH-Fmoc), 7.23 (dd, J = 2.0 and
8.8 Hz, 1H, CH-indole), 7.29 (br t, J = 7.6 Hz, 1H, CH-indole),
7.36ꢀ7.43 (br s, 1H, (CH-indole), 7.66 (d, J = 7.6 Hz, 2H, HC-Fmoc),
7.85 (d, J = 7.6 Hz, 2H, HC-Fmoc), 7.92 (br t, J = 7.6 Hz, 1H, CH-
indole), 10.48 (br s, 1H, NH-indole); 13C NMR (100 MHz, CD3CO-
CD3) δ (ppm): 43.7 (CHCO2H), 44.1 (CH2NH), 48.1 (OCH2CH),
67.0(OCH2), 112.8 (C-indole or C-Fmoc), 114.2, 120.8, 122.3, 125.7,
126.1, 127.9 (CH-Fmoc and CH-indole), 128.8, 136.2, 142.1, 145.2 (C-
indole or C-Fmoc), 157.3, 174.2 (CdO); HRMS (ESI) Calcd for
C26H22N2O4Br (MH+) 505.0763, found 505.0764.
20
AcOH (3/5/2/0.1%). Mp 90ꢀ91 °C; [R]D ꢀ45 (c 1.0, CH2Cl2); tR
(HPLC, column B, eluent II) 4.7 min; 99% ee: tR (HPLC, column C,
eluent III) 7.6 min; [tR enantiomer X (HPLC, column C, eluant III)
1
11.3 min]; MS (ESI) m/z: 445.1 [(M + H)+]; H NMR (400 MHz,
CD3COCD3) δ (ppm): 2.74 (br s, 1H, OH), 3.50 (m, 1H, HCHNH),
3.67 (m, 1H, HCHNH), 4.06 (m, 2H, CHCO2H and OCH2CH), 4.19
(d, J = 7.2 Hz, 2H, OCH2), 6.56 (br s, 1H, NH-Fmoc), 6.73 (td, J = 2.3
and 8.7 Hz, 1H, H-indole), 7.01 (dd, J = 2.3 and 10.0 Hz, 1H, H-indole),
7.14ꢀ7.19 (m, 3H, H-Fmoc and H-indole),), 7.30 (t, J = 7.4 Hz, 2H,
H-Fmoc), 7.53 (d, J = 7.5 Hz, 2H, H-Fmoc), 7.57 (dd, J = 5.4 and 8.7 Hz,
1H, H-indole), 7.71 (d, J = 7.5 Hz, 2H, H-Fmoc), 10.17 (br s, 1H, NH-
indole); 13C NMR (100 MHz, CD3COCD3) δ (ppm): 42.9 (CHCO2H),
43.2 (CH2NH), 47.2 (OCH2CH), 66.1 (OCH2), 97.3 and 97.54 (CH-
indole), 107.3 and 107.6 (CH-indole), 111.1, 117.9 (C-indole and
C-Fmoc), 119.9, 123.6, 125.2, 127.0, 127.6 (CH-Fmoc and CH-indole),
141.2, 144.3 (C-indole and C-Fmoc), 156.4, 158.6, 160.9 (CdO); HRMS
(ESI) Calcd for C26H22N2O4F (MH+) 445.1564, found 445.1567.
Transformation of Compound 7e into the (S)-3-(9-Fluor-
enylmethoxycarbonylamino)-2-(5-bromo-1H-indol-3-yl)-
propionic Acid (S)-13e. To a solution of compound 11e (190 mg,
0.3 mmol) in acetic acid (5 mL) were added at room temperature THF
(10 mL), water (2 mL), concentrated HCl (0.8 mL), and portionwise Zn
dust (250 mg, 3.8 mmol). The reaction mixture was vigorously stirred
for 1.5ꢀ2 h at the same temperature (monitored by HPLC, column B).
The suspension was filtered, and the filtrate was concentrated in vacuo.
The residue was diluted with CH2Cl2 and washed successively with
water and with saturated aqueous NaHCO3. The organic layer was then
dried over Na2SO4, and after removal of the solvent, the crude acetic acid
salt of the expected compound 14e (>99% yield) was obtained and used
without further purification;20 tR (HPLC, column B, eluent I) 2.38 min;
MS (ESI) m/z: 604.3 and 606.3 [(M + H)+].
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra of compounds 11aꢀe and 13aꢀe; HPLC chromatograms
of compounds 11aꢀe and 13aꢀe; HRMS spectra for compounds
11aꢀe, 13aꢀe, 15aꢀd, and 16e; ORTEP drawing and crystal
data for compound 7e. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: monique.calmes@univ-montp2.fr.
’ ACKNOWLEDGMENT
The authors thank the CNRS, the MESR, the AUF (fellowship
to N.P.), and the Ministry of Education and Science (Bulgaria)
(Grant DTK 02/61) for their financial support.
After N-Fmoc protection, the N-Fmoc-β-tryptophan ester (30R,2S)-
16e (115 mg, 0.14 mmol, 48% yield) was isolated as a white solid after
6123
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The Journal of Organic Chemistry
ARTICLE
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(14) The diastereoisomeric ratio was determined by 1H NMR and
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(15) Side products are detected by HPLC analysis of the crude
mixtures and are not isolated; in particular during investigation of the
differents parameters of the FriedelꢀCrafts reaction, alkylated products
are not isolated.
(16) See, for example: Jia, Y.-X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L.
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indoles with a nitroalkene, the Lewis acid slows the reaction (except
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of the Lewis acid additive allowed slight improvement of the selectivity.
(18) Although conversions of the nitroacrylate occurred with good
yields, enantiopure compounds 11aꢀe (ee >99%) were obtained in
moderate yields due in particular to the delicate separation of the
mixture of the main and minor diastereoisomers (30R,2S) and (30R,2R).
(19) This preferential conformation has been previously proposed
and should correspond to the nonchelated form of the two carbonyl
groups of pantolactone derivatives (Camps, P.; Munoz-Torrero, D. Curr.
Org. Chem. 2004, 8, 1339–1380); this arrangement is also found in the
various X-ray crystallography data of compounds previously prepared by
us using the same chiral auxiliary (see, for example: (a) Calmꢀes, M.;
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complicated, HPLC and LC/MS analyses were just used to characterize
these intermediate compounds.
(21) Three equivalents of LiOH was used to obtain quantitative
hydrolysis: the first equivalent to neutralize the amine salt, the second to
form the carboxylic acid salt, and the third to allow saponification of the
ester bond.
(22) Nicolaou, K. C.; Estrada, A. A.; Zak, M.; Lee, S. H.; Safina, B.
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layer chromatography (TLC) compound retention data were converted
into an isocratic elution or linear gradient elution system; CV: column
volume (mL).
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