Novel syntheses of chiral β- and γ-amino acid derivatives utilizing N-protected (aminoacyl)benzotriazoles from aspartic and glutamic acids

Article abstract of DOI:10.1021/jo061667s

Friedel-Crafts reactions of N-protected (α-aminoacyl)benzotriazoles with hetero- and benzenoid- aromatics give α-amino ketones that can be reduced by either triethyl silane or sodium borohydride to form the corresponding β- and γ-amino acid derivatives. T

Full text of DOI:10.1021/jo061667s

Novel Syntheses of Chiral â- and γ-Amino Acid Derivatives Utilizing
N-Protected (Aminoacyl)benzotriazoles from Aspartic and Glutamic
Acids
Alan R. Katritzky,* Hui Tao, Rong Jiang, Kazuyuki Suzuki, and Kostyantyn Kirichenko
Center for Heterocyclic Compounds, Department of Chemistry, UniVersity of Florida,
GainesVille, Florida 32611-7200
katritzky@chem.ufl.edu
ReceiVed August 10, 2006
Friedel-Crafts reactions of N-protected (R-aminoacyl)benzotriazoles with hetero- and benzenoid- aromatics
give R-amino ketones that can be reduced by either triethyl silane or sodium borohydride to form the
corresponding â- and γ-amino acid derivatives. The preservation of chirality throughout this process is
confirmed by chiral HPLC results.
Introduction
of various enzyme inhibitor γ-aminobutyric acid analogues.16-19
In addition, they are attractive starting materials for the
formation of peptides with helical secondary structures.20,21
Given this significance, the development of efficient methods
for the synthesis of enantiomerically pure â- and γ-amino acids
is important. Among previously reported methodologies for
â-amino acids,22 many use R-amino acids as starting materials
because of their ready availability, low cost, and high enantio-
meric purity. The extensively studied direct homologation of
R-amino acids to â-amino acids following the Arndt-Eistert
procedure23-27 is not suitable for large-scale synthesis because
Non-natural â- and γ-amino acids have attracted considerable
attention due to their important roles in the design and synthesis
of bioactive molecules and in the study of biomimetic polymers
that contain both secondary and tertiary structure analogous to
those of natural proteins. Thus, â-amino acid derivatives are
key components of a variety of biologically active molecules
including the antitumor agent taxol,1 antifungal jasplakinolide,2
antibiotics,3 and the enzyme inhibitor bestatin.4 â-Amino acids
are also of high interest as precursors for peptidomimetics5,6
and â-lactams.7,8 Likewise, γ-amino acids represent important
roles in the structure of natural products with antitumor activity
such as Hapalosin,9-11 Dolastatin, and12,13 Caliculins14,15 and
(11) Stratmann, K.; Burgoyne, D. L.; Moore, R. E.; Patterson, G. M. L.;
Smith, C. D. J. Org. Chem. 1994, 59, 7219.
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Chem. 1994, 59, 6127.
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Lett. 1991, 32, 5983.
(16) Burke, J. R.; Silverman, R. B. J. Am. Chem. Soc. 1991, 113, 9329.
(17) Margolin, A. L. Tetrahedron Lett. 1993, 34, 1239.
(18) Wei, Z.-Y.; Knaus, E. E. Tetrahedron 1994, 50, 5569.
(19) Denis, J. N.; Tchertchian, S.; Tomassini, A.; Vallee, Y. Tetrahedron
Lett. 1997, 38, 5503.
(1) Rowinsky, E. K.; Donehower, R. C. Pharmacol. Ther. 1991, 52, 35.
(2) Crews, P.; Manes, L. V.; Boehler, M. Tetrahedron Lett. 1986, 27,
2797.
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Carmichael, W. W. Tetrahedron Lett. 1989, 30, 4349.
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29, 100.
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Curr. Med. Chem. 2002, 9, 811.
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101, 3219.
(7) The Chemistry of â-Lactams; Page, M. I.; Ed.; Chapman and Hall:
London, 1992.
(8) The Organic Chemistry of â-Lactams; Georg, G. I., Ed.; Verlag
Chemie: New York, 1993.
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Soc. 1998, 120, 8569.
(9) Haddad, M.; Botuha, C.; Larcheveque, M. Synlett 1999, 1118.
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10.1021/jo061667s CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/15/2006
J. Org. Chem. 2007, 72, 407-414
407

Katritzky et al.
SCHEME 1. Literature Methods of Synthesis of â-Amino Acids
SCHEME 2. Literature Methods of Synthesis of γ-Amino Acids from r-Amino Acidsa
a Reagents and conditions: (a) Meldrum’s acid, DCC, DMAP; (b) NaBH4, AcOH; (c) toluene, reflux; (d) NaOH, acetone/water.
SCHEME 3. γ-Amino Acids from Glutamic Acids
of the high cost of the silver catalyst and difficulties associated
with handling of the hazardous reagent CH2N2.22 Although
Longobarbo’s modification avoids the use of silver catalyst and
CH2N2, the procedure requires four steps.28
Naturally occurring aspartic acid, possessing a â-amino
carboxylic acid fragment, is an attractive precursor for the
preparation of â-amino acids. In the literature, enantioselective
synthesis of â-amino acids was demonstrated by (i) the
stereoselective ring opening of either lactones or oxazolidinones
prepared in four steps from L-aspartic acid29-31 and the
nucleophilic substitution of organocuprates32 or organozinc
reagents,33 and (ii) the Mannich reaction of malonates with
N-Boc-imines in the presence of catalytic Cinchona alkaloid
derivatives34 (Scheme 1).
homologation,35,36 which has disadvantages as discussed above;
(ii) Wittig reaction of Ph3PdCHCO2Et with aldehydes available
from natural R-amino acids followed by reduction, which is
limited to γ-alkyl-γ-amino acid derivatives;37 (iii) reaction of
diethyl potassiomalonate with N-tosylaziridines generated in situ
from N,O-ditosyl-protected R-amino alcohols derived from
R-amino acids,38 but removal of the N-tosyl group in the
presence of sensitive functionalities may require harsh reaction
conditions (reflux in 47% aqueous HBr);38 and (iv) synthesis
of γ-substituted γ-amino acid via N-Boc-5-substituted pyrroli-
dinones, where the decarboxylative ring closure needs high
temperature (77-110 °C).39
Other reported syntheses of optically pure γ-amino acids
utilizing glutamic acids (Scheme 3) are (i) the nucleophilic
substitution of iodo derivatives of glutamic acid with organo-
cuprates32 and (ii) coupling of an organozinc reagent of glutamic
acid with aryl iodides in the presence of Pd.33 However, the
Four methods (Scheme 2) for the synthesis of γ-amino acids
from natural R-amino acids comprise (i) double Arndt-Eistert
(23) Seebach, D.; Overhand, M.; Kuhnle, F. N. M.; Martinoni, B.; Oberer,
L.; Hommel, U.; Widmer, H. HelV. Chim. Acta 1996, 79, 913.
(24) Guichard, G.; Abele, S.; Seebach, D. HelV. Chim. Acta 1998, 81,
187.
(25) Yuan, C.; Williams, R. M. J. Am. Chem. Soc. 1997, 119, 11777.
(26) Leggio, A.; Liguori, A.; Procopio, A.; Sindona, G. J. Chem. Soc.,
Perkin Trans. 1 1997, 13, 1969.
(27) Muller, A.; Voge, C.; Sewald, N. Synthesis 1998, 837.
(28) Caputo, R.; Cassano, E.; Longobardo, L.; Palumbo, G. Tetrahedron
1995, 51, 12337.
(29) Jefford, C. W.; McNulty, J.; Lu, Z.-H.; Wang, J. B. HelV. Chim.
(35) Chimiak, A. Rocz. Chim. 1969, 43, 299.
(36) Buchschacher, P.; Cassal, J. M.; Furst, A.; Meier, W. HelV. Chim.
Acta 1977, 2747.
(37) Hanessian, S.; Schaum, R. Tetrahedron Lett. 1997, 38, 163.
(38) Tseng, C. C.; Terashinma, S.; Yamada, S. Chem. Pharm. Bull. 1977,
25, 29.
Acta 1996, 79, 1203.
(30) Seki, M.; Matsumoto, K. Tetrahedron Lett. 1996, 37, 3165.
(31) Seki, M.; Shimizu, T.; Matsumoto, K. J. Org. Chem. 2000, 65, 1298.
(32) Marini, A. E.; Roumestant, M. L.; Viallefont, P.; Razafindramboa,
D.; Bonato, M.; Follet, M. Synthesis 1992, 1104.
(33) Dexter, C. S.; Jackson, R. F. W. J. Org. Chem. 1999, 64, 7579.
(34) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
(39) Smreina, M.; Majer, P.; Majerova, E.; Guerassina, T. A.; Eissenstat,
M. A. Tetrahedron 1997, 53, 12867.
408 J. Org. Chem., Vol. 72, No. 2, 2007

Syntheses of Chiral â- and γ-Amino Acid DeriVatiVes
SCHEME 4. Preparation of N-(Tfa-r-aminoacyl)benzotriazoles
use of organometallic reagents can be limited by incompatibility
with other functionality.32,33,39
SCHEME 5. Syntheses of γ-Keto-â-amino Esters 9a-f
Our group has developed N-acylbenzotriazoles as efficient
acylating agents for N-,40-45 C-,46-51 O-,49,52,53 and S-acylation
reactions.54 In particular, N-acylbenzotriazoles, which are
advantageously stable toward moisture and storable for a
relatively long period of time, are efficient for the C-acylation
of reactive heterocycles such as indoles, pyrroles,50 furan, and
thiophene51 in the presence of Lewis acid, such as AlCl3.
Recently, we have extended our work to the preparation of
N-Tfa- and Fmoc-R-amino ketones by C-acylation of pyrroles
and indoles with chiral N-protected (R-aminoacyl)benzotriaz-
oles42,44,55 in the presence of AlCl3 with preservation of chirality
as demonstrated by configurational analysis.56
We now report a novel and practical method for the synthesis
of ω-aryl substituted â- (10-12) and γ-amino acid derivatives
(14,15) by the Friedel-Crafts acylation of aromatics with chiral
N-protected 1-(R-aminoacyl)benzotriazoles 4 and 8 (generated
from L-aspartic or L-glutamic acid) followed by reduction of
the intermediate ketones, with preservation (>99%) of the
chirality.
Results and Discussion
Preparation of 1-(N-Tfa-R-aminoacyl)benzotriazoles 4 and
8. L-Aspartic acid (1) was reacted with methanol and thionyl
chloride to form the γ-mono methyl ester 2 selectively in 80%
yield.57 Ester 2 was protected with a N-trifluoroacetyl (Tfa) group
using ethyl trifluoroacetate in the presence of Et3N (2 equiv) in
methanol to generate N-Tfa-aspartic monoester 3.58 On treatment
with thionyl chloride (1 equiv) and benzotriazole (3 equiv), ester
3 gave Tfa-Asp(OMe)-Bt (4) in 80-91% yield. Similarly, Tfa-
Glu(OMe)-Bt (8) was simply synthesized in 66% overall yield
from L-glutamic acid 5 via intermediates 6 and 7 (Scheme 4).
Syntheses of γ-Keto-â-amino Esters 9. Previously, we
reported the synthesis of R-amino ketones via Friedel-Craft
acylation of N-heterocycles utilizing chiral N-protected (R-
aminoacyl)benzotriazoles in the presence of AlCl3.56 Unfortu-
nately, attempted extension of this method to the preparation
of γ-keto-â-amino esters 9 by acylation of aromatics with Tfa-
Asp(OMe)-Bt (4) failed, resulting in decomposition of the latter.
Screening Lewis Acids led us to TiCl4 (starting materials were
recovered when BF3 or ZnBr2 was used). The reaction of Tfa-
Asp(OMe)-Bt (4) with aromatics (1.1 equiv) in the presence of
TiCl4 (1.5 equiv) at 20 °C for 1-3 h gave the expected amino
γ-keto-â-amino esters 9a-f in 35-89% yield (Scheme 5, Table
1).
(40) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65,
8210.
(41) Katritzky, A. R.; Levell, J. R.; Pleynet, D. P. M. Synthesis 1998,
153-156.
(42) Katritzky, A. R.; Wang, M.; Yang, H.; Zhang, S.; Akhmedov, N.
G. ArkiVoc 2002, Viii, 134.
(43) Katritzky, A. R.; Rogovoy, B. V.; Kirichenko, N.; Vvedensky, V.
Bioorg. Med. Chem. Lett. 2002, 12, 1809.
(44) Katritzky, A. R.; Suzuki, K.; Singh, S. K. Synthesis 2004, 2645.
(45) Katritzky, A. R.; Hoffmann, S.; Suzuki, K. ArkiVoc 2004, xii, 14.
(46) Katritzky, A. R.; Pastor, A. J. Org. Chem. 2000, 65, 3679.
(47) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem.
2003, 68, 1443.
(48) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem.
2003, 68, 4932.
(49) Katritzky, A. R.; Wang, Z.; Wang, M.; Wilkerson, C. R.; Hall, C.
D.; Akhmedov, N. G. J. Org. Chem. 2004, 69, 6617.
(50) Katritzky, A. R.; Suzuki, K.; Sandeep K. Singh, J. Org. Chem. 2003,
68, 5720.
(51) Katritzky, A. R.; Suzuki, K.; Singh, S. K. Croat. Chem. Acta 2004,
175.
γ-Aryl-â-amino Esters 10b,e,f, and 12 and γ-Aryl-â-amino
Acid 11 from the Reduction of γ-Keto-â-amino Esters 9.
Reaction of alkanophenone derivatives 9e,f with triethyl silane
(2.5 equiv) in the presence of trifluoroacetic acid (12.0 equiv)
gave the corresponding γ-aryl-â-amino esters 10e,f in 79% and
78% yield, respectively (Scheme 6).59
(52) Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J. Heterocycl. Chem.
1999, 36, 777.
(53) Wedler, C.; Kleiner, K.; Kunath, A.; Schick, H. Liebigs Ann. 1996,
881.
(54) Katritzky, A. R.; Shestopalov, A. A.; Suzuki, K. Synthesis 2004,
1806.
(55) Katritzky, A. R.; Angrish, P.; Hu¨r, D.; Suzuki, K. Synthesis 2005,
3, 397.
(57) Cox, R. J.; Hadfield, A. T.; Mayo-Martin, M. B. Chem. Commun.
2001, 1710.
(58) Curphey, T. J. J. Org. Chem. 1979, 44, 2805.
(59) West, C. T.; Donnelly, S. J.; Kooistra, D. A.; Doyle, M. P. J. Org.
Chem. 1973, 38, 2675.
(56) Katritzky, A. R.; Jiang, R.; Suzuki, K. J. Org. Chem. 2005, 4993.
J. Org. Chem, Vol. 72, No. 2, 2007 409

Katritzky et al.
SCHEME 9. Syntheses of δ-Keto-γ-amino Esters 13
TABLE 1. Syntheses of γ-Keto-â-amino Esters 9a-f
entry
aromatics
γ-keto-â-amino esters 9 (%)
a
b
c
d
e
f
indole
67-82
74-89
65
54
35
N-methylindole
N-methylpyrrole
pyrrole
1,3-(MeO)2C6H4
1,3,5-(MeO)3C6H3
50
TABLE 2. Syntheses of δ-Keto-γ-amino Esters 13
SCHEME 6. γ-Aryl-â-amino Esters 10e,f from the
Reduction of γ-Keto-â-amino Esters 9e,f
entry
aromatics
δ-keto-γ-amino esters 13 (%)
a
b
c
d
e
f
Indole
70
59
56
61
46
46
N-methylindole
N-methylpyrrole
pyrrole
1,3-(MeO)2C6H4
1,3,5-(MeO)3C6H3
SCHEME 10. δ-Aryl-γ-amino Esters 14 from the Reduction
of δ-Keto-γ-amino Esters 13
SCHEME 7
SCHEME 11. δ-Aryl-γ-amino Acids 15 from the Reduction
of δ-Keto-γ-amino Esters 13
SCHEME 8
However, attempted reduction of γ-keto-â-amino esters 9a-d
with triethyl silane in the presence of trifluoroacetic acid resulted
in no reaction and recovery of the starting ketones. When γ-keto-
â-amino ester 9a was treated with 4 molar equiv of sodium
borohydride in 75% aqueous DMF solution, the corresponding
γ-(indol-3-yl)-â-amino acid 11 was isolated in 70% yield
(Scheme 7).60 Unlike 9a, attempted reduction of N-methylindol-
3-yl derivative 9b resulted in complex set of products.
The attempted reduction of DL-9b with dimethylchlorosilane
in the presence of catalytic indium chloride (0.2 equiv) in
dichloromethane under reflux gave a low level of initial
conversion of DL-9b to the target DL-10b (progress of the
reaction was monitored by TLC using ethyl acetate/hexanes,
1:3) followed by disappearance of DL-10b and formation of a
new spot (non-rising) on TLC after reflux for a prolonged time
(Scheme 8). Addition of indium chloride (0.8 equiv) followed
by reflux for 36 h allowed complete reduction of DL-9b to give
the 1-methylindoline derivative DL-12 (70%, as a mixture
diastereoisomers). This suggests deactivation of indium chloride
due to formation of a complex (non-rising spot on TLC) with
the indoline nitrogen of DL-12. Compound DL-12 was reoxidized
to γ-(N-methylindol-3-yl)-â-amino ester DL-10b in 85% yield
with active manganese dioxide (5 equiv) in toluene at 20 °C.
Similar reduction/oxidation of L-9b, without isolation of
intermediate 12, gave L-10b in 56% yield (Scheme 8).
Syntheses of δ-Keto-γ-amino Esters 13. Following the
method developed for the preparation of γ-keto-â-amino esters
9, the reaction of Tfa-Glu(OMe)-Bt (8) with aromatics (1.1
equiv) in the presence of TiCl4 (1.5 equiv) at 20 °C for 1 h
produced the corresponding δ-keto-γ-amino esters 13 in 46-
70% yield (Scheme 9, Table 2).
δ-Aryl-γ-amino Esters 14 and δ-Aryl-γ-amino Acids 15
from the Reduction of δ-Keto-γ-amino Esters 13. The
reduction of δ-keto-γ-amino esters 13e,f by triethylsilane in the
presence of trifluoroacetic acid gave the corresponding δ-aryl-
γ-amino esters 14e,f in 84% and 88% yield, respectively
(Scheme 10).59 The reduction of δ-keto-γ-amino esters 13a,b
by sodium borohydride in 75% aqueous DMF solution provided
the corresponding δ-aryl-γ-amino acids 15a,b in 87% and 73%
yield, respectively (Scheme 11).60
Configurational Study of γ-Aryl-â-amino Acid 11 and
δ-Aryl-γ-amino Acid 15. Since the key feature of biologically
active amino acid derivatives is associated with the absolute
configuration of the carbon R to the amino group, total control
of chirality represents a major goal in the synthesis of amino
acid derivatives. To evaluate the chiral integrity of these
reactions, we synthesized DL-4-(1-methyl-1H-indole-3-yl)-3-
(2,2,2-trifluoroacetamido)butanoic acid DL-11 and DL-5-(1-
methyl-1H-indole-3-yl)-4-(2,2,2-trifluoroacetamido)pentanoic acid
DL-15b starting from DL-aspartic or DL-glutamic acid, respec-
(60) Haldar, P.; Ray, J. K. Tetrahedron Lett. 2003, 44, 8229.
410 J. Org. Chem., Vol. 72, No. 2, 2007

Syntheses of Chiral â- and γ-Amino Acid DeriVatiVes
mmol) and aromatics (1.1 mmol) in anhydrous dichloromethane
(10 mL) was added anhydrous 1 M TiCl4 in dichloromethane (1.5
mL) at 0 °C. The mixture was stirred at room temperature for 1-3
h, and saturated aqueous sodium bicarbonate and charcoal were
added. The mixture was stirred for 10-15 min and filtered. The
product was extracted with dichloromethane, and the extract was
washed successively with aqueous sodium bicarbonate and water,
dried over magnesium sulfate, and after concentration under reduced
pressure, purified by column chromatography on silica gel to give
9a-f.
tively. The chirality control in the synthesis of γ-aryl-â-amino
acid 11 was confirmed by comparison of chiral HPLC chro-
matograms of L-11 with DL-11 (CHIROBIOTIC T column;
eluted with 0.1% TEAA solution in 30% aqueous methanol;
flow rate 0.5 mL/min at room temperature; UV detection at
210 nm), which showed two signals of equal intensity for DL-
11 at 14.2 and 16.9 min and the single peak at 16.9 min for
L-11. Similarly, comparison of the chiral HPLC of DL-15b (two
distinct peaks of equal intensity at 13.2 and 13.7 min) with L-15b
(one peak at 13.7 min) obtained under the same conditions
(CHIROBIOTIC T column; eluted with 0.1% TEAA solution
in 60% aqueous methanol (v/v); flow rate 0.4 mL/min at room
temperature; UV detection at 210 nm) demonstrated full chiral
preservation (>99%) in the synthesis of δ-aryl-γ-amino acids
15.
(S)-Methyl 4-(Indol-3-yl)-4-oxo-3-(2,2,2-trifluoroacetamido)-
butanoate (9a). Gradient column chromatography using dichlo-
romethane-dichloromethane/methanol (50:1); beige microcrystals
from chloroform (67-82%, three experiments), mp 148-150 °C;
[R]23D ) -83.6° (c 2.44, chloroform); 1H NMR δ 9.47 (br s, 1H),
8.32-8.28 (m, 1H), 8.11 (d, J ) 3.0 Hz, 1H), 8.05 (d, J ) 8.0 Hz,
1H), 7.43-7.39 (m, 1H), 7.31-7.27 (m, 2H), 5.68-5.62 (m, 1H),
3.70 (s, 3H), 2.99 (dd, J ) 16.0, 5.2 Hz, 1H), 2.86 (dd, J ) 16.0,
6.0 Hz, 1H); 13C NMR δ 188.9, 171.3, 157.0 (q, J ) 38.4 Hz),
136.5, 133.4, 125.6, 124.4, 123.4, 122.0, 115.7 (q, J ) 288.0 Hz),
114.0, 111.9, 52.4, 51.5, 37.2. Anal. Calcd for C15H13F3N2O4: C,
52.64; H, 3.83; N, 8.18. Found: C, 52.98; H, 3.86; N, 8.01.
Methyl 4-(1H-indol-3-yl)-4-oxo-3-(2,2,2-trifluoroacetamido)-
butanoate (DL-9a). Beige microcrystals from diethyl ether (78%),
Conclusion
Novel â- and γ-amino acid derivatives can be readily
synthesized from aspartic and glutamic acid through their
corresponding benzotriazole intermediates. Full preservation of
chirality in these sequences was supported by chiral HPLC
results.
1
mp 142-144 °C; H NMR (acetone-d6) δ 10.74 (br s, 1H), 8.43
(d, J ) 8.4 Hz, 1H), 8.34-8.29 (m, 1H), 8.22 (d, J ) 3.3 Hz, 1H),
7.50-7.44 (m, 1H), 7.31-7.25 (m, 2H), 5.74-5.67 (m, 1H), 3.68
(s, 3H), 3.07 (dd, J ) 16.1, 6.0 Hz, 1H), 2.86 (dd, J ) 16.1, 6.3
Experimental Section
Hz, 1H); 13C NMR (acetone-d6)
δ 188.8, 170.7, 156.4
Melting points were determined on a hot-stage apparatus and
are uncorrected. NMR spectra were obtained in CDCl3 (unless
(q, J ) 37.8 Hz), 136.7, 133.5, 125.7, 123.7, 122.6, 121.8, 115.6
(q, J ) 287.4 Hz), 113.8, 111.9, 51.8, 51.1, 36.4. Anal. Calcd for
C15H13F3N2O4: C, 52.64; H, 3.83; N, 8.18. Found: C, 52.99; H,
3.79; N, 8.22.
1
otherwise stated) with TMS as the internal standard for H (300
MHz) or the solvent as the internal standard for 13C (75 MHz).
Amino acids were used as supplied without additional purification.
THF was used freshly distilled from sodium/benzophenone. All of
the reactions were carried out under nitrogen. Column chromatog-
raphy was performed on silica gel 200-425 mesh.
Methyl 4-(1-Methyl-1H-indol-3-yl)-4-oxo-3-(2,2,2-trifluoro-
acetamido)butanoate (9b). Column chromatography using dichlo-
romethane/ethyl acetate 20:1; white needles from diethyl ether (74-
89%, three experiments), mp 153-154 °C; [R]23D ) -79.4° (c 2.4,
chloroform); 1H NMR δ 8.33-8.29 (m, 1H), 8.05 (s, 1H), 8.02 (d,
J ) 8.9 Hz, 1H), 7.37-7.30 (m, 3H), 5.63 (dt, J ) 8.3, 5.8 Hz,
1H), 3.87 (s, 3H), 3.70 (s, 3H), 2.99 (dd, J ) 16.0, 5.6 Hz, 1H),
2.83 (dd, J ) 16.0, 5.9 Hz, 1H); 13C NMR δ 188.4, 171.0, 156.7
(q, J ) 37.8 Hz), 137.7, 137.1, 126.4, 124.0, 123.4, 122.3, 115.7
(q, J ) 288.0 Hz), 112.7, 110.0, 52.2, 51.3, 37.1, 33.8. Anal. Calcd
for C16H15F3N2O4: C, 53.94; H, 4.24; N, 7.86. Found: C, 53.88;
H, 4.13; N, 7.79.
General Procedure for the Preparation of N-Tfa-(Aminoa-
cyl)benzotriazoles 4 and 8. To a solution of benzotriazole (0.95
g, 6 mmol) in dichloromethane was added SOCl2 (0.24 g, 2 mmol),
and the reaction mixture was heated under reflux for 30 min. The
reaction mixture was cooled to 0 °C, and the appropriate acid 3 or
7 (2 mmol) in dichloromethane (10 mL) was added dropwise. The
reaction mixture was stirred at 20-25 °C for 2 h and filtered. The
filtrate was washed with saturated aqueous Na2CO3 (until benzo-
triazole was completely removed) and dried over magnesium
sulfate. The solvent was removed under vacuum to give the product
4 or 8, suitable for further Friedel-Crafts acylation.
Methyl 4-(1-Methylindol-3-yl)-4-oxo-3-(2,2,2-trifluoroaceta-
mido)butanoate (DL-9b). Needles from diethyl ether (70%), mp
1
Methyl (3S)-4-(Benzotriazol-1-yl)-4-oxo-3-(2,2,2-trifluoroac-
etamido)butanoate (4). Colorless needles from diethyl ether (80-
133-134 °C; H NMR δ 8.33-8.29 (m, 1H), 8.04 (s, 1H), 8.01
(br s, 1H), 7.37-7.30 (m, 3H), 5.63 (dt, J ) 8.2, 5.8 Hz, 1H), 3.85
(s, 3H), 3.69 (s, 3H), 2.98 (dd, J ) 16.0, 5.6 Hz, 1H), 2.83 (dd, J
) 16.0, 6.0 Hz, 1H); 13C NMR δ 188.4, 171.0, 156.7 (q, J ) 37.8
Hz), 137.7, 137.1, 126.4, 124.0, 123.3, 122.3, 115.7 (q, J ) 287.4
Hz), 112.7, 110.0, 52.2, 51.3, 37.1, 33.8. Anal. Calcd for
C16H15F3N2O4: C, 53.94; H, 4.24; N, 7.86. Found: C, 53.61; H,
4.26; N, 7.52.
1
91%); mp 68-70 °C; H NMR δ 8.27 (d, J ) 8.2 Hz, 1H), 8.17
(d, J ) 8.2 Hz, 1H), 7.88 (br s, 1H), 7.73 (apparent t, 1H), 7.58
(apparent t, 1H), 6.08-6.14 (m, 1H), 3.69 (s, 3H), 3.53 (dd, J )
17.3, 5.1 Hz, 1H), 3.30 (dd, J ) 17.3, 4.9 Hz, 1H); 13C NMR δ
170.3, 167.4, 157.0 (q, J ) 38 Hz), 146.0, 131.3, 131.1, 127.0,
120.6, 115.5 (q, J ) 288 Hz), 114.3, 52.5, 50.4, 36.3. Anal. Calcd
for C13H11F3N4O4: C, 45.36; H, 3.22; N, 16.28. Found: C, 45.48;
H, 3.23; N, 15.91.
Methyl (3S)-4-(1-Methyl-pyrrol-3-yl)-4-oxo-3-(2,2,2-trifluo-
roacetamido)butanoate (9c). Column chromatography using ethyl
Methyl (4S)-5-(Benzotriazol-1-yl)-5-oxo-4-(2,2,2-trifluoroac-
etamido)pentanoate (8). Colorless needles from chloroform/
acetate/hexanes 1:3, colorless needles from chloroform/hexanes
1
(65%), mp 70-71 °C; [R]23 ) -68.7° (c 2.53, chloroform); H
D
hexanes (93%); mp 50-52 °C; [R]23 ) -49.04° (c 6.67,
NMR δ 7.73 (d, J ) 6.3 Hz, 1H), 7.15 (dd, J ) 4.2, 1.5 Hz, 1H),
6.95 (s, 1H), 6.21 (dd, J ) 4.2, 2.4 Hz, 1H), 5.57-5.51 (m, 1H),
3.94 (s, 3H), 3.70 (s, 3H), 2.98 (dd, J ) 15.9, 5.1 Hz, 1H), 2.82
(dd, J ) 15.9, 6.0 Hz, 1H); 13C NMR δ 183.8, 170.4, 156.5 (q, J
) 38.1 Hz), 133.3, 127.2, 121.0, 115.7 (q, J ) 286.3 Hz), 109.3,
52.2 (d, J ) 2.9 Hz), 51.2, 37.7 (d, J ) 8.6 Hz). Anal. Calcd for
C12H13F3N2O4: C, 47.07; H, 4.28; N, 9.15. Found: C, 46.91; H,
4.21; N, 9.24.
D
chloroform); 1H NMR δ 8.17 (d, J ) 8.4 Hz, 1H), 8.05 (d, J ) 3.2
Hz, 1H), 7.99 (t, J ) 8.0 Hz, 1H), 7.59 (t, J ) 8.0 Hz, 1H), 7.29
(s, 1H), 5.98-6.04 (m, 1H), 3.71 (s, 3H), 2.44-2.55 (m, 2H), 2.0-
2.37 (m, 2H); 13C NMR δ 174.0, 168.8, 157.4 (q, J ) 39.0 Hz),
146.0, 131.2, 130.9, 126.9, 120.5, 115.6 (q, J ) 287.4 Hz), 114.2,
53.4, 52.4, 30.1, 26.4. Anal. Calcd for C14H13F3N4O4: C, 46.93;
H, 3.66; N, 15.64. Found: C, 46.95; H, 3.64; N, 14.91.
General Procedure for the Preparation of â-Keto-â-amino
Esters 9a-f. To a solution of Tfa-Asp(OMe)-Bt (4) (0.34 g, 1
(S)-Methyl 3-(2,2,2-Trifluoroacetamido)-4-oxo-4-(1H-pyrrol-
3-yl)butanoate (9d). Column chromatography using ethyl acetate/
J. Org. Chem, Vol. 72, No. 2, 2007 411

Katritzky et al.
hexanes 1:3, colorless needles (54%), mp 135-136 °C, [R]23
)
luoroacetamido)butanoic acid L-11 (220 mg, 70%), beige microc-
D
-31.9° (c 0.8, chloroform); 1H NMR δ 9.74 (br s, 1H), 7.85 (d, J
) 7.8 Hz, 1H), 7.16-7.13 (m, 2H), 6.38-6.35 (m., 1H), 5.58-
5.51 (m, 1H), 3.69 (s, 3H), 2.99 (dd, J ) 16.2, 5.4 Hz, 1H), 2.88
(dd, J ) 16.2, 5.4 Hz, 1H); 13C NMR δ 183.6, 170.6, 156.7 (q, J
) 37.5 Hz), 128.4, 127.0, 118.5, 115.6 (q, J ) 285.8 Hz), 111.9,
52.3 (q, J ) 2.85 Hz), 50.7, 37.0. Anal. Calcd for C11H11F3N2O4:
C, 45.21; H, 3.79; N, 9.59. Found: C, 45.44; H, 3.76; N, 9.24.
Methyl (3S)-4-(2,4-Dimethoxyphenyl)-4-oxo-3-(2,2,2-trifluo-
roacetamido)butanoate (9e). Column chromatography using dichlo-
romethane, colorless needles from chloroform/hexanes (35%), mp
109-110 °C, [R]23D ) -2.6° (c 0.8, chloroform); 1H NMR δ 7.84
(d, J ) 7.5 Hz, 1H), 7.74 (d, J ) 7.2 Hz, 1H), 6.60 (d, J ) 2.1 Hz,
1H), 6.57 (d, J ) 2.1 Hz, 1H), 6.47 (d, J ) 2.1 Hz, 1H), 5.72-
5.66 (m, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.64 (s, 3H), 3.05 (dd, J
) 16.2, 4.5 Hz, 1H), 2.80 (dd, J ) 16.2, 5.7 Hz, 1H); 13C NMR δ
193,8, 170.5, 165.7, 160.4, 156.6 (q, J ) 37.0 Hz), 134.0, 116.8,
115.7 (q, J ) 286.3 Hz), 106.3, 98.0, 55.6 (2C), 52.0 (2C), 35.9.
Anal. Calcd for C15H16F3NO6: C, 49.59; H, 4.44; N, 3.86. Found:
C, 49.20; H, 4.39; N, 3.77.
rystals from dichloromethane, mp 189-191 °C, [R]23 ) 8.8° (c
D
2.2, acetone); 1H NMR (acetone-d6) δ 10.09 (br s, 1H), 8.49 (d, J
) 7.6 Hz, 1H), 7.70 (d, J ) 7.8 Hz, 1H), 7.39 (d, J ) 7.8 Hz, 1H),
7.22 (s, 1H), 7.13-7.02 (m, 2H), 4.71-4.59 (m, 1H), 3.20-3.06
(m, 2H), 2.72 (d, J ) 6.6 Hz, 2H); 13C NMR (acetone-d6) δ 172.9,
157.2 (q, J ) 36.6 Hz), 137.7, 128.7, 124.5, 122.3, 119.7, 119.4,
117.1 (q, J ) 288.0 Hz), 112.3, 111.5, 49.3, 38.0, 30.3. Anal. Calcd
for C14H13F3N2O3: C, 53.51; H, 4.17; N, 8.91. Found: C, 53.36;
H, 4.25; N, 8.87.
4-(1H-Indol-3-yl)-3-(2,2,2-trifluoroacetamido)butanoic Acid
(DL-11). White microcrystals from dichloromethane (86%), mp
1
176-178 °C; H NMR (acetone-d6) δ 10.09 (br s, 1H), 8.47 (d, J
) 6.9 Hz, 1H), 7.70 (d, J ) 7.7 Hz, 1H), 7.39 (d, J ) 8.0 Hz, 1H),
7.23 (s, 1H), 7.14-7.02 (m, 2H), 4.70-4.60 (m, 1H), 3.20-3.07
(m, 2H), 2.73 (d, J ) 6.4 Hz, 2H); 13C NMR (acetone-d6) δ 172.9,
157.2 (q, J ) 36.6 Hz), 137.7, 128.7, 124.5, 122.4, 119.7, 119.4,
117.1 (q, J ) 288.0 Hz), 112.3, 111.6, 49.3, 38.0, 30.3. Anal. Calcd
for C14H13F3N2O3: C, 53.51; H, 4.17; N, 8.91. Found: C, 53.57;
H, 4.33; N, 8.81.
(S)-Methyl 4-Oxo-3-(2,2,2-trifluoroacetamido)-4-(2,4,6-tri-
methoxyphenyl)butanoate (9f). Microcrystals from diethyl ether
Reduction of DL-9b to DL-12 with Chlorodimethylsilane in
the Presence of Indium Chloride. A mixture of methyl 4-(1-
methyl-indol-3-yl)-4-oxo-3-(2,2,2-trifluoroacetamido)butanoate DL-
9b (0.36 g, 1 mmol), indium chloride (220 mg, 1 mmol), and
chlorodimethylsilane (added in three portions every 12 h; total 0.9
mL, 0.77 g, 8 mmol) in dichloromethane (40 mL) was gently heated
under reflux under nitrogen for 36 h. After cooling, saturated
aqueous sodium bicarbonate and charcoal was added; the mixture
was stirred for 30 min and filtered. The organic layer was separated,
dried over magnesium sulfate, and concentrated under vacuum to
dryness. The residue was purified by column chromatography on
silica gel using gradient ethyl acetate/hexanes eluent (1:4 f 1:3)
to give two diastereoisomers of methyl 4-(1-methylindolin-3-yl)-
3-(2,2,2-trifluoroacetamido)butanoate DL-12 (total yield 65%). First
(45-50%), mp 90-92 °C, [R]23 ) -13.4° (c 2.56, chloroform);
D
1H NMR δ 7.75 (d, J ) 8.0 Hz, 1H), 6.11 (s, 2H), 5.44-5.37 (m,
1H), 3.83 (s, 3H), 3.79 (s, 6H), 3.63 (s, 3H), 2.95-2.81 (m, 2H);
13C NMR δ 196.7, 170.5, 163.6, 159.2, 156.4 (q, J ) 37.8 Hz),
115.6 (q, J ) 288.0 Hz), 107.9, 90.4, 55.7, 55.3, 51.8, 34.7. Anal.
Calcd for C16H18F3NO7: C, 48.86; H, 4.61; N, 3.56. Found: C,
48.61; H, 4.74; N, 3.49.
Procedure for the Preparation of γ-Aryl-â-amino Esters 10e,f.
To a solution γ-keto-â-amino esters 9e,f (1 mmol) in dichlo-
romethane (10 mL) at 20 °C was added trifluoroacetic acid (0.45
mL, 6 mmol) followed by triethylsilane (0.8 mL, 5 mmol). After 4
h of stirring at room temperature, water was added, and the product
was extracted with ethyl acetate. The extract was dried over
magnesium sulfate and concentrated under vacuum. The residue
was purified by column chromatography on silica gel using gradient
ethyl acetate/hexanes (1:6 f 1:3) to give 10e,f.
(R)-Methyl 3-(2,2,2-trifluoroacetamido)-4-(2,4-dimethoxyphe-
nyl)butanoate (10e). Colorless needles from chloroform/hexanes
(79%), mp 87-88 °C, [R]23D ) 5.7° (c 0.88, chloroform); 1H NMR
δ 7.61 (d, J ) 6.9 Hz, 1H), 7.01 (d, J ) 8.7 Hz, 1H), 6.47-6.43
(m, 2H), 4.44-4.35 (m, 1H), 3.82 (s. 3H), 3.80 (s, 3H), 3.71 (s,
3H), 2.98-2.85 (m, 2H), 2.65 (dd, J ) 16.2, 4.5 Hz, 1H), 2.52
(dd, J ) 16.5, 6.6 Hz, 1H); 13C NMR δ 171.7, 160.2, 158.0, 156.9
(q, J ) 36.5 Hz), 131.8, 117.0, 115.8 (q, J ) 286.3 Hz), 104.6,
98.6, 55.3, 55.2, 51.8, 48.4, 36.5, 32.9. Anal. Calcd for C15H18F3-
NO5: C, 51.58; H, 5.19; N, 4.01. Found: C, 51.38; H, 5.18; N,
3.92.
(R)-Methyl 3-(2,2,2-Trifluoroacetamido)-4-(2,4,6-trimethox-
yphenyl)butanoate (10f). Beige microcrystals from diethyl ether
(78%), mp 116-118 °C, [R]23D ) 7.2° (c 2.5, chloroform); 1H NMR
δ 7.60 (d, J ) 6.6 Hz, 1H), 6.14 (s, 2H), 4.40-4.31 (m, 1H), 3.81
(s, 3H), 3.80 (s, 6H), 3.71 (s, 3H), 2.98 (dd, J ) 13.8, 8.0 Hz, 1H),
2.90 (dd, J ) 13.8, 4.9 Hz, 1H), 2.64 (dd, J ) 16.2, 4.8 Hz, 1H),
2.54 (dd, J ) 16.2, 6.7 Hz, 1H); 13C NMR δ 171.5, 160.4, 158.8,
156.6 (q, J ) 36.0 Hz), 115.8 (q, J ) 288.6 Hz), 105.1, 90.4, 55.4,
55.3, 51.6, 48.1, 36.8, 25.7. Anal. Calcd for C16H20F3NO6: C, 50.66;
H, 5.31; N, 3.69. Found: C, 50.77; H, 5.33; N, 3.64.
Reduction of γ-Indol-3-yl-â-amino Ester 9a with Sodium
Borohydride. To a stirred solution of 9a (330 mg, 1 mmol) in
75% aqueous DMF (13 mL) was added sodium borohydride (150
mg, 4 mmol) at 0 °C. The reaction mixture was stirred for 2 h at
20 °C, cooled to 0 °C, diluted with water, and acidified with 1 N
hydrochloric acid to pH 5. The product was extracted with ethyl
acetate, and the extract was washed with water, dried over
magnesium sulfate, and concentrated under vacuum. The residue
was purified by column chromatography on silica gel using ethyl
acetate/hexanes (1:1) to give (R)-4-(1H-indol-3-yl)-3-(2,2,2-trif-
1
isomer: oil (45%); H NMR δ 7.44 (d, J ) 8.9 Hz, 1H), 7.10 (t,
J ) 7.7 Hz, 1H), 7.01 (d, J ) 7.3 Hz, 1H), 6.68 (t, J ) 7.4 Hz,
1H), 6.48 (d, J ) 7.7 Hz, 1H), 4.48-4.36 (m, 1H), 3.71 (s, 3H),
3.50 (t, J ) 8.4 Hz, 1H), 3.23-3.13 (m, 1H), 3.02 (dd, J ) 8.7,
7.1 Hz, 1H), 2.73 (s, 3H), 2.72-2.56 (m, 2H), 2.15 (ddd, J ) 14.1,
10.7, 3.7 Hz, 1H), 1.75 (ddd, J ) 14.1, 10.5, 3.7 Hz, 1H); 13C
NMR δ 171.8, 157.0 (q, J ) 36.9 Hz), 152.9, 132.3, 128.0, 123.0,
117.8, 115.8 (q, J ) 288.0 Hz), 107.4, 61.3, 52.0, 44.9, 38.1, 37.7,
37.5, 35.8. Anal. Calcd for C16H19F3N2O3: C, 55.81; H, 5.56; N,
8.14. Found: C, 55.79; H, 6.14; N, 7.58. Second isomer: oil (20%);
1H NMR δ 7.42 (d, J ) 8.8 Hz, 1H), 7.18-7.10 (m, 2H), 6.71 (t,
J ) 7.4 Hz, 1H), 6.50 (d, J ) 7.8 Hz, 1H), 4.51-4.40 (m, 1H),
3.71 (s, 3H), 3.39 (t, J ) 8.4 Hz, 1H), 3.20-3.11 (m, 1H), 3.04
(dd, J ) 8.5, 5.4 Hz, 1H), 2.73 (s, 3H), 2.65 (dd, J ) 16.6, 4.8 Hz,
1H), 2.56 (dd, J ) 16.6, 4.8 Hz, 1H), 2.00-1.94 (m, 2H); 13C NMR
δ 171.9, 156.7 (q, J ) 36.6 Hz), 152.6, 132.2, 128.1, 123.9, 118.1,
115.8 (q, J ) 288.0 Hz), 107.7, 62.2, 52.0, 45.3, 38.0, 37.8, 37.5,
36.0. Anal. Calcd for C16H19F3N2O3: C, 55.81; H, 5.56; N, 8.14.
Found: C, 55.44; H, 5.92; N, 7.83.
Oxidation to DL-10b. A mixture of the diastereoisomers of
methyl 4-(1-methylindolin-3-yl)-3-(2,2,2-trifluoroacetamido)bu-
tanoate DL-12 (175 mg, 0.5 mmol) with active manganese dioxide
(400 mg, 4 mmol) in toluene (20 mL) was stirred under nitrogen
until the starting material was consumed (10-12 h; progress of
the reaction was monitored by TLC). The mixture was filtered and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel using gradient ethyl acetate/hexanes
eluent (1:3 f 2:5) to give methyl 4-(1-methyl-1H-indol-3-yl)-3-
(2,2,2-trifluoroacetamido)butanoate DL-10b (145 mg, 85%), beige
microcrystals from diethyl ether, mp 106-107 °C; 1H NMR δ 7.61
(d, J ) 8.0 Hz, 1H), 7.32-7.22 (m, 3H), 7.16-7.11 (m, 1H), 6.88
(s, 1H), 4.63-4.52 (m, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.16 (dd, J
) 14.5, 5.6 Hz, 1H), 3.04 (dd, J ) 14.5, 8.2 Hz, 1H), 2.66-2.53
(m, 2H); 13C NMR δ 172.0, 156.6 (q, J ) 37.0 Hz), 137.0, 127.7,
127.5, 121.9, 119.2, 118.6, 115.7 (q, J ) 288.0 Hz), 109.3, 108.8,
412 J. Org. Chem., Vol. 72, No. 2, 2007

Syntheses of Chiral â- and γ-Amino Acid DeriVatiVes
51.9, 47.6, 35.9, 32.6, 28.9. Anal. Calcd for C16H17F3N2O3: C,
56.14; H, 5.01; N, 8.18. Found: C, 56.43; H, 5.38; N, 8.14.
Reduction/Oxidation of L-9b to L-10b. The mixture of (S)-
methyl 4-(1-methyl-1H-indol-3-yl)-4-oxo-3-(2,2,2-trifluoroaceta-
mido)butanoate L-9b (0.36 g, 1 mmol), indium chloride (220 mg,
1 mmol), and chlorodimethylsilane (added in three portions every
12 h; total 0.9 mL, 0.77 g, 8 mmol) in dichloromethane (40 mL)
was heated under reflux under nitrogen for 36 h. After cooling,
saturated aqueous sodium bicarbonate and charcoal were added,
and the mixture was stirred for 30 min, and filtered. The organic
layer was separated, dried over magnesium sulfate, and concentrated
under vacuum to dryness. The residue of (3R)-methyl 4-(1-
methylindolin-3-yl)-3-(2,2,2-trifluoroacetamido)butanoate L-12 (not
purified) was dissolved in toluene (30 mL), and active manganese
dioxide (870 mg, 10 mmol) was added at 20 °C. The mixture was
stirred under nitrogen at 20 °C until the starting material was
consumed (10-12 h, filtered, and concentrated under vacuum. The
residue was purified by column chromatography on silica gel using
gradient dichloromethane f dichloromethane/ethyl acetate (20:1)
to give (R)-methyl 4-(1-methyl-indol-3-yl)-3-(2,2,2-trifluoroaceta-
mido)butanoate L-10b (190 mg, 56%), beige microcrystals from
diethyl ether, mp 115-116 °C, [R]23D ) 2.95° (c 2.1, chloroform);
1H NMR δ 7.60 (d, J ) 7.9 Hz, 1H), 7.33-7.20 (m, 3H), 7.15-
7.10 (m, 1H), 6.87 (s, 1H), 4.561-4.51 (m, 1H), 3.73 (s, 3H), 3.68
(s, 3H), 3.14 (dd, J ) 14.6, 5.6 Hz, 1H), 3.02 (dd, J ) 14.6, 8.1
Hz, 1H), 2.58 (d, J ) 5.2 Hz, 2H); 13C NMR δ 172.0, 156.6 (q, J
) 37.2 Hz), 137.0, 127.7, 127.5, 121.9, 119.3, 118.6, 115.7 (q, J
) 287.5 Hz), 109.3, 108.9, 51.9, 47.6, 35.9, 32.6, 28.9. Anal. Calcd
for C16H17F3N2O3: C, 56.14; H, 5.01; N, 8.18. Found: C, 55.91;
H, 5.10; N, 7.96.
Hz, 1H), 6.95 (s, 1H), 6.24-6.22 (m, 1H), 5.40 (dt, J ) 8.1, 3.0
Hz, 1H), 3.95 (s, 3H), 3.70 (s, 3H), 2.49-2.36 (m, 3H), 2.04-
1.89 (m, 1H); 13C NMR δ 185.6, 173.2, 157.2 (d, J ) 37.0 Hz),
135.5, 127.6, 121.7, 116.0 (d, J ) 286.3 Hz), 109.6, 53.9, 52.0,
37.8, 29.9, 29.6.
Methyl (4S)-5-(1H-Pyrrol-2-yl)-5-oxo-4-(2,2,2-trifluoroaceta-
mido)pentanoate (13d). Colorless microcrystals from chloroform/
hexanes (61%), mp 81-82 °C; [R]23D ) 38.70° (c 2.0, chloroform);
1H NMR δ 9.74 (br s, 1H), 7.56 (br s, 1H), 7.27-7.24 (m, 1H),
7.17-7.15 (m, 1H), 6.40-6.37 (m, 1H), 5.43-5.37 (m, 1H), 3.72
(s, 3H), 2.53-2.39 (m, 3H), 2.01-1.94 (m, 1H); 13C NMR δ 185.1,
173.3, 157.2 (q, J ) 37.0 Hz), 128.6, 126.9, 118. 9, 115.7 (q, J )
285.7 Hz), 111.9, 53.5, 52.0, 29.6, 29.5. Anal. Calcd for
C12H13F3N2O4: C, 47.07; H, 4.28; N, 9.15. Found: C, 46.91; H,
4.19; N, 8.75.
Methyl (4S)-5-(2,4-Dimethoxyphenyl)-5-oxo-4-(2,2,2-trifluo-
roacetamido)pentanoate (13e). Colorless needles from chloroform/
hexanes (46%), mp 137 °C, [R]23 ) 7.29° (c 1.40, chloroform);
D
1H NMR δ 7.94 (d, J ) 9.0 Hz, 1H), 7.66 (d, J ) 7.5 Hz, 1H),
6.60 (dd, J ) 9.0, 2.1 Hz, 1H), 6.48 (d, J ) 2.4 Hz, 1H), 5.71-
5.66 (m, 1H), 3.97 (s, 3H), 3.89 (s, 3H), 3.64 (s, 3H), 2.44-2.26
(m, 3H), 1.96-1.88 (m, 1H); 13C NMR δ 194.5, 173.0, 166.1, 161.2,
156.9 (q, J ) 37.0 Hz), 134.1, 116.4, 115.8 (q, J ) 285.7 Hz),
106.3, 98.3, 57.5, 55.8, 55.7, 51.8, 29.8, 27.2. Anal. Calcd for
C16H18F3NO6: C, 50.93; H, 4.81; N, 3.71. Found: C, 50.97; H,
4.78; N, 3.70.
(S)-Methyl 4-(2,2,2-Trifluoroacetamido)-5-(2,4,6-trimethox-
yphenyl)-5-oxopentanoate (13f). Colorless needles from chloroform/
1
hexanes (46%), mp 99-100 °C; H NMR δ 7.55 (d, J ) 7.5 Hz,
1H), 6.13 (s, 2H), 5.36-5.30 (m, 1H), 3.84 (s, 3H), 3.80 (s, 6H),
3.64 (s, 3H), 2.37-2.27 (m, 3H), 2.03-1.90 (m, 1H); 13C NMR δ
198.4, 173.0, 163.7, 159.3, 156.7 (q, J ) 37.0 Hz), 115.6 (q, J )
285.7 Hz), 108.1, 90.5, 58.5, 55.7 (2C), 55.3, 51.5, 29.2, 26.1. Anal.
Calcd for C17H20F3NO7: C, 50.13; H, 4.95; N, 3.44. Found: C,
50.13; H, 4.93; N, 3.40.
General Procedure for the Preparation of δ-Keto-γ-amino
esters 13. To a solution of Tfa-Glu(OMe)-Bt (8) (0.34 g, 1 mmol)
and aromatics (1.1 mmol) in anhydrous dichloromethane (10 mL)
was added anhydrous 1 M TiCl4 in dichloromethane (1.5 mL) at 0
°C. The mixture was stirred at room temperature for 1-2 h and
purified by chromatography (dry loading method, ethyl acetate/
hexanes 1:3) to give 13a-f.
General Procedure for the Preparation of δ-Aryl-γ-amino
Esters 14e,f. To γ-keto-γ-amino ester 13e,f (1 mmol) in dichlo-
romethane were added trifluoroacetic acid (0.45 mL) and triethyl-
silane (0.4 mL, 2.5 mmol). After 4 h of stirring at room temperature,
water was added, and the mixture was extracted with diethyl ether.
The ether layer was dried with magnesium sulfate. The solvent was
removed under vacuum, and the residue was purified by chroma-
tography (ethyl acetate/hexanes 1:6).
Methyl (4S)-5-(1H-Indol-3-yl)-5-oxo-4-(2,2,2-trifluoroaceta-
mido)pentanoate (13a). Light yellow microcrystals from chloroform/
hexanes (70%); mp 132-133 °C, [R]23 ) 4.50° (c 2.0, chloro-
D
1
form); H NMR δ 9.26 (br s, 1H), 8.35-8.32 (m, 2H), 7.76 (d, J
) 7.5 Hz, 1H), 7.46-7.43 (m, 1H), 7.36-7.31 (m, 2H), 5.55-
5.49 (m, 1H), 3.72 (s, 3H), 2.54-2.42 (m, 3H), 1.97-1.92 (m,
1H); 13C NMR δ 190.5, 173.7, 157.6 (q, J ) 37.6 Hz), 136.4, 133.5,
125.5, 124.4, 123.4, 122.1, 115.8 (q, J ) 285.8 Hz), 114.2, 111.8,
54.1, 52.0, 30.2, 29.4. Anal. Calcd for C16H15F3N2O4: C, 53.94;
H, 4.24; N, 7.86. Found: C, 54.22; H, 4.27; N, 7.69.
Methyl (4S)-5-(2,4-Dimethoxyphenyl)-4-(2,2,2-trifluoroaceta-
mido)pentanoate (14e). Beige microcrystals from dichloromethane
1
(84%), mp 85-86 °C, [R]23 ) -8.33° (c 1.92, chloroform); H
D
NMR δ 7.06-7.00 (m, 2H), 6.46-6.43 (m, 2H), 4.16-4.04 (m,
1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.67 (s, 3H), 2.83-2.80 (m, 2H),
2.51-2.31 (m, 2H), 2.01-1.77 (m, 2H); 13C NMR δ 173.7, 160.1,
157.9, 157.0 (q, J ) 36.4 Hz), 131.7, 117.3, 115.9 (q, J ) 288.3
Hz), 104.6, 98.6, 55.4, 55.2, 51.8, 51.7, 33.8, 30.6, 29.1. Anal. Calcd
for C16H20F3NO5: C, 52.89; H, 5.55; N, 3.85. Found: C, 53.18;
H, 5.71; N, 3.72.
Methyl (4S)-5-(1-Methyl-indol-3-yl)-5-oxo-4-(2,2,2-trifluoro-
acetamido)pentanoate (13b). Colorless needles from chloroform/
hexanes (59%), mp 137-139 °C, [R]23 ) 15.3° (c 2.0, chloro-
D
1
form); H NMR δ 8.32-8.35 (m, 1H), 8.21 (s, 1H), 7.89 (d, J )
7.5 Hz, 1H), 7.33-7.36 (m, 3H), 5.45-5.51 (m, 1H), 3.88 (s, 3H),
3.71 (s, 3H), 2.40-2.55 (m, 3H), 1.93-2.01 (m, 1H); 13C NMR δ
190.2, 173.6, 157.5 (q, J ) 37.1 Hz), 137.8, 137.6, 126.6, 124.2,
123.5, 122.5, 116.0 (q, J ) 286.3 Hz), 112.9, 110.2, 54.3, 52.1,
34.0, 30.3, 29.6. Anal. Calcd for C17H17F3N2O4: C, 55.14; H, 4.63;
N, 7.56. Found: C, 55.04; H, 4.61; N, 7.44.
(S)-Methyl 4-(2,2,2-Trifluoroacetamido)-5-(2,4,6-trimethox-
yphenyl)pentanoate (14f). Colorless microcrystals from chloroform/
1
hexanes (88%), mp 88-89 °C; H NMR δ 7.15 (d, J ) 7.0 Hz,
1H), 6.13 (s, 2H), 4.04-3.98 (m, 1H), 3.81 (s, 3H), 3.80 (s, 6H),
3.68 (s, 3H), 2.87 (dd, J ) 13.9, 3.9 Hz, 1H) 2.76 (dd, J ) 13.9,
9. 5 Hz, 1H), 2.55-2.35 (m, 2H), 2.04-1.84 (m, 2H); 13C NMR δ
173.9, 160.2, 158.6, 157.1 (q, J ) 36.5 Hz), 115.9 (q, J ) 286.9
Hz), 105.5, 90.4, 55.5 (2C), 55.3, 51.7, 51.6, 30.6, 29.5, 26.4. Anal.
Calcd for C17H22F3NO6: C, 51.91; H, 5.64; N, 3.56. Found: C,
51.72; H, 5.61; N, 3.44.
Methyl 5-(1-Methyl-indol-3-yl)-5-oxo-4-(2,2,2-trifluoroaceta-
mido)pentanoate (DL-13b). Beige microcrystals from dichlo-
romethane (83%), mp 170-173 °C; 1H NMR δ 8.35-8.33 (m, 1H),
8.22 (s, 1H), 7.71 (d, J ) 7.4 Hz, 1H), 7.38-7.34 (m, 3H), 5.49-
5.43 (m, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 2.54-2.39 (m, 3H), 1.99-
1.91 (m, 1H); 13C NMR δ 190.0, 173.4, 157.3 (q, J ) 37.8 Hz),
137.6, 137.4, 126.4, 124.0, 123.4, 122.3, 115.8 (q, J ) 288.0 Hz),
112.6, 110.0, 54.0, 51.9, 33.9, 30.3, 29.4.
General Procedure for the Preparation of δ-Aryl-γ-amino
Acids 15a,b. NaBH4 (0.05 g, 1.3 mmol) was added to a solution of
γ-keto-γ-amino ester 13a,b (0.33mmol) in 75% aqueous DMF (13
mL). The mixture was stirred at room temperature for 1.5 h and
quenched with water (15 mL). Then the reaction mixture was
acidified with 1 N aqueous hydrochloric acid to pH 5, followed by
Methyl (4S)-5-(1-Methylpyrrol-3-yl)-5-oxo-4-(2,2,2-trifluoro-
acetamido)pentanoate (13c). Colorless needles from chloroform/
hexanes (56%), mp 131-132 °C, [R]23 ) 13.73° (c 0.83,
D
chloroform); 1H NMR δ 7.59 (d, J ) 6.0 Hz, 1H), 7.29 (d, J ) 3.9
J. Org. Chem, Vol. 72, No. 2, 2007 413

Katritzky et al.
extraction with ethyl acetate. The organic layer was washed with
water and dried over sodium sulfate. After removing solvent, the
product was purified by recrystallization from chloroform/hexane.
(4S)-5-(1H-Indol-3-yl)-4-(2,2,2-trifluoroacetamido)pentano-
3.72 (s, 3H), 2.89 (d, J ) 6.9 Hz, 2H), 2.25-2.18 (m, 2H), 1.85-
1.75 (m, 2H); 13C NMR (DMSO-d6) δ 174.0, 156.1 (q, J ) 36.1
Hz), 136.6, 127.8, 127.7, 121.1, 118.5, 118.4, 116.0 (q, J ) 288.6
Hz), 109.8, 109.6, 50.6, 32.3, 30.5, 29.7, 28.3. Anal. Calcd for
C16H17F3N2O3: C, 56.04; H, 5.01; N, 8.18. Found: C, 56.01; H,
5.22; N, 7.56.
ic Acid (15a). Beige microcrystals from chloroform/hexanes (87%);
1
mp 127-130 °C; [R]23 ) 14.48° (c 0.67, chloroform); H NMR
D
(DMSO-d6) δ 12.10 (br s, 1H), 10.85 (s, 1H), 9.27 (d, J ) 8.4 Hz,
1H), 7.55 (d, J ) 7.7 Hz, 1H), 7.33 (d, J ) 8.0 Hz, 1H), 7.12-
6.96 (m, 3H), 4.14-3.98 (m, 1H), 2.91 (d, J ) 7.0 Hz, 2H), 2.31-
2.16 (m, 2H), 1.92-1.73 (m, 2H); 13C NMR (DMSO-d6) δ 174.1,
156.1 (q, J ) 36.0 Hz), 136.2, 127.4, 123.3, 121.0, 118.4, 118.3,
116.0 (q, J ) 288.6 Hz), 111.4, 110.5, 50.5, 30.5, 29.8, 28.5. Anal.
Calcd for C15H15F3N2O3: C, 54.88; H, 4.61; N, 8.53. Found: C,
54.64; H, 4.71; N, 8.35.
5-(1-Methylindol-3-yl)-4-(2,2,2-trifluoroacetamido)pentano-
ic Acid (DL-15b). Beige microcrystals from chloroform/hexanes
(56%), mp 148-150 °C; 1H NMR (DMSO-d6) δ 12.10 (br s, 1H),
9.28 (d, J ) 8.5 Hz, 1H), 7.56 (d, J ) 7.8 Hz, 1H), 7.37 (d, J )
8.1 Hz, 1H), 7.16-7.10 (m, 2H), 7.02 (t, J ) 7.4 Hz, 1H), 4.10-
3.94 (m, 1H), 3.73 (s, 3H), 2.90-2.88 (m, 2H), 2.30-2.12 (m,
2H), 1.90-1.67 (m, 2H); 13C NMR (DMSO-d6) δ 174.0, 156.1 (q,
J ) 36.1 Hz), 136.6, 127.8, 127.7, 121.1, 118.5, 118.4, 116.0 (q,
J ) 288.6 Hz), 109.8, 109.6, 50.6, 32.3, 30.5, 29.7, 28.3. Anal.
Calcd for C16H17F3N2O3: C, 56.14; H, 5.01; N, 8.18. Found: C,
55.95; H, 5.03; N, 8.32.
(4S)-5-(1-Methyl-1H-indol-3-yl)-4-(2,2,2-trifluoroacetamido)-
pentanoic Acid (15b). Beige microcrystals from chloroform/
hexanes (73%); mp 185-186 °C; [R]23 ) 12.24° (c 0.67,
D
chloroform); 1H NMR (DMSO-d6) δ 12.09 (br s, 1H), 9.27 (d, J )
8.5 Hz, 1H), 7.56 (d, J ) 7.7 Hz, 1H), 7.37 (d, J ) 8.1 Hz, 1H),
7.16-7.09 (m, 2H), 7.02 (t, J ) 7.6 Hz, 1H), 4.04-3.99 (m, 1H),
JO061667S
414 J. Org. Chem., Vol. 72, No. 2, 2007