1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenylpropan-1-ones: Mosher-Bt reagents

Article abstract of DOI:10.1021/jo070278a

(Chemical Equation Presented) Benzotriazole derivatives of 3,3,3-trifluoro-2-methoxy-2-phenylpropionic acid react with water-soluble amino acids and peptides in an acetonitrile/water (2:1) mixture to give the corresponding amides in quantitative yield.

Full text of DOI:10.1021/jo070278a

SCHEME 1. Synthesis of 1-Benzotriazol-1-yl-3,3,3-
trifluoro-2-methoxy-2-phenylpropan-1-one
1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-
phenylpropan-1-ones: Mosher-Bt Reagents
Alan R. Katritzky,*,§ Prabhu P. Mohapatra,§
Dmytro Fedoseyenko,§ Matthew Duncton,¶ and
Peter J. Steel£
Center for Heterocyclic Compounds, Department of Chemistry,
UniVersity of Florida, GainesVille, Florida 32611-7200, RenoVis
Inc., 2 Corporate DriVe, South San Francisco, California
94080, and Chemistry Department, UniVersity of Canterbury,
Christchurch, New Zealand
acid chlorides are unstable or difficult to prepare;11 thus N-(R-
protected-amino) acylbenzotriazoles provide a simple and
efficient method to prepare peptides.12 They also enable the
preparation of esters and amides from unprotected hydroxyaro-
matic and -aliphatic carboxylic acids,13 chiral O-(R-protected-
aminoacyl) steroids,14 1,3-benzodioxin-4-one and benzoxazine-
2,4-diones,15 alkyl, unsaturated, (hetero)aryl, and N-protected
R-amino ketones, and (R-aminoacyl)oxy-substituted terpenes and
alkanes.16
katritzky@chem.ufl.edu
ReceiVed February 9, 2007
Mosher’s reagent, R-methoxy-R-trifluoromethylphenyl acetic
acid (MTPA), reported in 1973 is now the preferred chiral
(10) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Gromova, A. V.; Witek,
R.; Steel, P. J. J. Org. Chem. 2005, 70, 9211.
(11) Caprio, V. In ComprehensiVe Organic Functional Group Trans-
formations II; Katritzky, A. R., Taylor, R. J. K., Eds.; Elsevier: New York,
2005; p 135.
(12) (a) Katritzky, A. R.; Suzuki, K.; Singh, S. K. Synthesis 2004, 2645.
(b) Katritzky, A. R.; Angrish, P.; Hu¨r, D.; Suzuki, K. Synthesis 2005, 398.
(c) Katritzky, A. R.; Angrish, P.; Suzuki, K. Synthesis 2006, 411. (d)
Katritzky, A. R.; Todadze, E.; Cusido, J.; Angrish, P.; Shestopalov, A. A.
Chem. Biol. Drug Des. 2006, 68, 37. (e) Katritzky, A. R.; Todadze, E.;
Shestopalov, A. A.; Cusido, J.; Angrish, P. Chem. Biol. Drug Des. 2006,
68, 42. (f) Katritzky, Alan, R.; Meher, G.; Angrish, P. Chem. Biol. Drug
Des. 2006, 68, 326.
(13) Katritzky, A. R.; Singh, S. K.; Cai, C.; Bobrov, S. J. Org. Chem.
2006, 71, 3364.
(14) Katritzky, A. R.; Angrish, P. Steroids 2006, 71, 660.
(15) Katritzky, A. R.; Singh, S. K.; Akhmedova, R.; Cai, C.; Bobrov, S.
ARKIVOC 2007, Vi, 6.
(16) (a) Katritzky, A. R.; Le, K. N. B.; Khelashvili, L.; Mohapatra, P.
P. J. Org. Chem. 2006, 71, 9861. (b) Katritzky, A. R.; Angrish, P. Synthesis
2006, 4135.
(17) (a) Kusumi, T.; Ooi, T.; Ohkubo, Y.; Yabuuchi, T. Bull. Chem.
Soc. Jpn. 2006, 79, 965. (b) Furusawa, M.; Hashimoto, T.; Noma, Y.;
Asakawa, Y. Chem. Pharm. Bull. 2006, 54, 996. (c) Barreiros, M. L.; David,
J. M.; David, J. P. Quim. NoVa 2005, 28, 1061. (d) Seco, J. M.; Quin˜oa´,
E.; Riguera, R. Chem. ReV. 2004, 104, 17. (e) Omata, K.; Fujiwara, T.;
Kabuto, K. Tetrahedron: Asymmetry 2002, 13, 1655. (f) Kubota, T.; Tsuda,
M.; Kobayashi, J. Org. Lett. 2001, 3, 1363. (g) Morohashi, A.; Satake, M.;
Nagai, H.; Oshima, Y.; Yasumoto, T. Tetrahedron 2000, 56, 8995. (h)
Chang, L. C.; Chavez, D.; Song, L. L.; Farnsworth, N. R.; Pezzutto, J. M.;
Kinghorn, A. D. Org. Lett. 2000, 2, 515. (i) Murata, M.; Matsuoka, S.;
Matsumori, N.; Paul, G. K.; Tachibana, K. J. Am. Chem. Soc. 1999, 121,
870. (j) Rossouw, W.; Hundt, A. F.; Steenkamp, J. A.; Ferreira, D.
Tetrahedron 1994, 50, 12477. (k) Rieser, M. J.; Hui, Y.; Rupprecht, J. K.;
Kozlowski, J. F.; Wood, K. V.; McLaughlin, J. L.; Hanson, P. R.; Zhuang,
Z.; Hoye, T. R. J. Am. Chem. Soc. 1992, 114, 10203. (l) Ohtani, I.; Kusumi,
T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092. (m)
Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32, 7165. (n) Ohtani, I.;
Kusumi, T.; Ishitsuka, M. O.; Kakisawa, H. Tetrahedron Lett. 1989, 30,
3147. (o) Kusumi, T.; Ohtani, I.; Inouye, Y.; Kakisawe, H. Tetrahedron
Lett. 1988, 29, 4731. (p) Trost, B. M.; Belletire, J. L.; Godleski, S.;
McDougal, P. G.; Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello,
G. S.; Varga, S. L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370. (q)
Yasuhara, F.; Yamaguchi, S.; Kasai, R.; Tanaka, D. Tetrahedron Lett. 1986,
27, 4033. (r) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
(s) Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38,
2143. (t) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543. (u) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1968, 90, 3732.
Benzotriazole derivatives of 3,3,3-trifluoro-2-methoxy-2-
phenylpropionic acid react with water-soluble amino acids
and peptides in an acetonitrile/water (2:1) mixture to give
the corresponding amides in quantitative yield.
N-Acylbenzotriazoles, well-established as activated deriva-
tives of carboxylic acids,1 are easily prepared directly from
carboxylic acids by either of two alternative methods: (i)
treatment with thionyl chloride and 1H-benzotriazole (BtH)2 or
(ii) with BtSO2Me in the presence of Et3N. They have been
applied for the N-acylation of amines3 and amides,3,4 the
O-acylation of aldehydes,5 and the C-acylation of ketones and
heteroaromatics,6 alkyl sulfones,7 alkyl cyanides,8 alkylazines,9
and R-nitroalkanes.10 Acylations with stable, crystalline N-
acylbenzotriazoles are of special utility when the corresponding
§ University of Florida.
¶ Renovis Inc.
£ University of Canterbury.
(1) Katritzky, A. R.; Suzuki, K.; Wang, Z. Synlett 2005, 1656.
(2) (a) Katritzky, A. R.; Zhang, Y.; Singh, S. K. Synthesis 2003, 2795.
(b) Katritzky, A. R.; Meher, N. K.; Cai, C.; Singh, S. K. ReV. Soc. Quim.
Mex. 2004, 48, 275.
(3) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210.
(4) Katritzky, A. R.; Yang, H.; Zhang, S.; Wang, M. ARKIVOC 2002,
xi, 39.
(5) Katritzky, A. R.; Pastor, A.; Voronkov, M. V. J. Heterocycl. Chem.
1999, 36, 777.
(6) (a) Katritzky, A. R.; Pastor, A. J. Org. Chem. 2000, 65, 3679. (b)
Katritzky, A. R.; Jiang, R.; Suzuki, K. J. Org. Chem. 2005, 70, 4993. (c)
Katritzky, A. R.; Meher, N. K.; Singh, S. K. J. Org. Chem. 2005, 70, 7792.
(7) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem.
2003, 68, 1443.
(8) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Wang, M. J. Org. Chem.
2003, 68, 4932.
(9) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Akhmedova, R. G.
ARKIVOC 2005, Vi, 329.
10.1021/jo070278a CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/26/2007
4268
J. Org. Chem. 2007, 72, 4268-4271

TABLE 1. Reactions of Mosher-Bt Reagent 1 with Chiral Amino
Acids and Di- and Tripeptides
FIGURE 1. MTPA amides of (R)-phenylalanine.
nylpropan-1-one (rac)-, (R)-, and (S)-1 (Mosher-Bt reagent) from
the corresponding MTPA and 1H-benzotriazole (BtH) and
studied their reactions with representative water-soluble chiral
amino acids and di- and tripeptides in acetonitrile/water (2:1)
medium in order to find their efficiency as stable chiral
derivatizing agents in place of the sensitive MTPA chlorides.
The reaction of (rac)-3,3,3-trifluoro-2-methoxy-2-phenylpro-
pionic acid (MTPA) with thionyl chloride and 1H-benzotriazole
(BtH) afforded the benzotriazole derivative, (rac)-1-benzotriazol-
1-yl-3,3,3-trifluoro-2-methoxy-2-phenylpropan-1-one (rac)-1 as
white crystals (mp 99-100 °C), in 95% yield (Scheme 1). The
detailed molecular structure of (rac)-1 was established by single-
crystal X-ray diffraction analysis (see Supporting Information).
The chiral versions of the Mosher-Bt reagent (R)-1-benzot-
riazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenylpropan-1-one (R)-1
and (S)-1-benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-
propan-1-one (S)-1 were easily prepared from (R)-MTPA and
(S)-MTPA in 95% yield (Scheme 1).
Reaction of (rac)-1-benzotriazol-1-yl-3,3,3-trifluoro-2-meth-
oxy-2-phenylpropan-1-one (rac)-1 with water-soluble amino
acids such as (R)-phenylalanine in an acetonitrile/water (2:1)
mixture at rt for 12 h gave the corresponding amide (R)-3-
phenyl-2-((R,S)-3,3,3-trifluoro-2-methoxy-2-phenylpropiony-
lamino)propionic acid (R,R)- and (S,R)-2a in 96% yield. The
1H NMR spectra of (R,R)- and (S,R)-2a showed the disappear-
ance of the Bt signals in the aromatic region, indicating the
loss of the benzotriazolyl group during the reaction. The 13C
NMR spectra of (R,R)- and (S,R)-2a showed three signals at
175.3, 166.9, and 166.8 ppm corresponding to the carbonyl
groups of the product and the disappearance of the signal at
165.7 ppm belonging to the carbonyl group at the R position of
the benzotriazolyl group in the starting material (rac)-1.
Similarly, reaction of (R)-1 and (S)-1 with (R)-phenylalanine
in an acetonitrile/water (2:1) mixture at rt for 12 h gave (R)-
3-phenyl-2-((R)-3,3,3-trifluoro-2-methoxy-2-phenylpropiony-
lamino)propionic acid (R,R)-2a and (R)-3-phenyl-2-((S)-3,3,3-
trifluoro-2-methoxy-2-phenylpropionylamino)propionic acid (S,R)-
2a, respectively, each in 96% yield. Reaction of (R)-1 with
(R)-tryptophan, dipeptide Gly-(R)-Phe-OH, and tripeptide Gly-
(S)-Phe-(S)-Phe-OH in an acetonitrile/water (2:1) mixture at rt
for 12 h gave (R)-3-(1H-indol-3-yl)-2-((R)-3,3,3-trifluoro-2-
methoxy-2-phenylpropionylamino)propionic acid (R,R)-2b,
(R)-3-phenyl-2-[2-((R)-3,3,3-trifluoro-2-methoxy-2-phenylpro-
pionylamino)acetylamino]propionic acid (R,R)-2c, and (S)-3-
phenyl-2-{(R)-3-phenyl-2-[2-((R)-3,3,3-trifluoro-2-methoxy-
2-phenylpropionylamino)acetylamino]propionylamino}-
propionic acid (R,S,S)-2d, respectively, in 98, 97, and 91% yield
(Table 1).
a Isolated yields of pure products.
derivatizing agent for determining both enantiomeric excess and
absolute configurations of synthetic and naturally occurring
chiral alcohols and amines by NMR spectroscopy.17 It is
commercially available both as the acid and as the acid
chloride.18 The procedure for determining the absolute config-
uration starts with the derivatization of a chiral alcohol (or
amine) of unknown configuration with (R)- and (S)-MTPA
chloride to yield a pair of diastereoisomeric esters (or amides).
1
The 19F, H, or 13C NMR chemical shifts of the diastereomers
are then acquired and compared. The absolute configuration of
the chiral compound is assigned by interpretation of the signs
of ∆δ values, using empirical models.17
Both enantiomers of commonly used MTPA chloride as chiral
derivatizing agents are commercially available; however, they
are costly, corrosive, moisture sensitive, and need to be stored
tightly closed in a deep freeze. To overcome these problems,
we have now prepared the racemic and both enantiomeric
versions of 1-benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phe-
(18) Although derivatization of an alcohol (or amine) with (R)-MTPA
acid gives the corresponding (R)-MTPA ester (or amide), the widely used
(R)-MTPA acid chloride gives the corresponding (S)-MTPA ester (or amide).
(a) Joshi, B. S.; Pelletier, S. W. Heterocycles 1999, 51, 183. (b) Joshi, B.
S.; Newton, M. G.; Lee, D. W.; Barber, A. D.; Pelletier, S. W. Tetrahe-
dron: Asymmetry 1996, 7, 25.
Straightforward assignment of the absolute configuration of
(R)-phenylalanine using the Mosher-Bt reagent was carried out.
J. Org. Chem, Vol. 72, No. 11, 2007 4269

1
TABLE 2. Chemical Shift (δ) Values in the H, 13C, and 19F NMR of MTPA Amides of (R)-Phenylalanine
δ values
δ values
(13C NMR)
δ values
product
Mosher
amide
(1H NMR)
(19F NMR)
abs.
config.
entry
methylene
methine
methylene
methine
CF3
1
2
(R,R)-2a
(S,R)-2a
(R,R)
(S.R)
difference
3.28, 3.14
3.24, 3.06
0.04, 0.08
4.93
5.03
0.1
37.6
37.4
0.2
55.4, 55.3
55.0, 55.0
0.4, 0.3
-69.37
-69.31
0.06
1H NMR analysis of the diastereomers (R,R)-2a and (S,R)-2a
[MTPA amides of (R)-phenylalanine, Figure 1a and b] shows
a significant difference in the chemical shift of the methine and
methylene signals (Table 2). This difference in chemical shift
is because, in one structure, the methine proton and the phenyl
ring of the MTPA moiety are on the same side of the MTPA
plane shown by dotted lines (Figure 1a), while in the other
diastereomer, they are opposite to each other (Figure 1b). The
diamagnetic effect of the phenyl ring of the MTPA moiety is
more pronounced in the structure where the methine group is
on the same side of the phenyl ring (4.93 δ, shielded, Figure
1a) as compared to the structure where the methine group is on
the opposite sides of the MTPA plane (5.03 δ, less shielded,
Figure 1b). Consequently, the 5.03 δ methine signal should
belong to the diastereomer (S,R)-2a (Figure 1b) and 4.93 δ
should belong to the diastereomer (R,R)-2a (Figure 1a).
To demonstrate that racemization does not occur during the
reaction, Mosher amides (R,R)- and (S,R)-2a, and (R,R)-2a and
(S,R)-2a were subjected to HPLC analysis. As determined by
chiral HPLC (using Chirobiotic T column, detection at 254 nm,
flow rate 0.1 mL/min, solvent MeOH), (R,R)-2a and (S,R)-2a
showed single peaks at 6.2 and 6.5 min, respectively, whereas
the diastereomeric mixture (R,R)- and (S,R)-2a showed two
peaks.
Mosher-Bt reagents can also be used to determine enantio-
meric excess of chiral amines. In order to demonstrate this
ability, we reacted a mixture of (R)- and (S)-phenylalanine (3:1
ratio) with the Mosher-Bt reagent (R)-1. HPLC analysis of the
resulting product showed two peaks and their area in the
expected 3:1 ratio.
Unfortunately, reaction of (rac)-1-benzotriazol-1-yl-3,3,3-
trifluoro-2-methoxy-2-phenylpropan-1-one (rac)-1 with alcohols
such as R-methylbenzyl alcohol and cholesterol did not give us
the desired Mosher ester even under microwave heating condi-
tions. Thus Mosher-Bt reagents are not applicable to deter-
mine enantiomeric excess and absolute configuration of chiral
alcohols.
Compared to the corresponding acid chlorides of Mosher-Bt
reagents, (rac)-, (R)-, and (S)-1 have the following advantages:
(i) they are noncorrosive, stable to moisture and heat, and can
be stored at room temperature indefinitely; thus they are easy
to handle as compared to corrosive and moisture-sensitive
MTPA chloride; (ii) the carboxyl groups of the amino acids,
di- and tripeptides need no protection prior to making their
MTPA amides; (iii) high yields of corresponding Mosher’s
amides are obtained (see Table 1); (iv) their reactions can be
carried out in aqueous conditions; (v) unlike MTPA chloride,
the absolute configurations of the Mosher-Bt reagent and
Mosher’s ester or amide are the same simplifying assignment
of absolute configuration; and (vi) they are easily prepared in
quantitative yield from the corresponding MTPA (250 mg, $36)
using 1H-benzotriazole (100 g, $25) and are thus more cost-
effective as compared to commercially available MTPA chloride
(250 mg, $100).
Experimental Section
General Procedure for Synthesis of 1: 3,3,3-Trifluoro-2-
methoxy-2-phenylpropionic acid (MTPA) (0.75 g, 3.2 mmol) and
thionyl chloride (3 mL) were refluxed together for 50 h. After excess
thionyl chloride was removed by vacuum evaporation at rt, the
residual oil was dissolved in dry dichloromethane (20 mL) and 3
equiv of 1H-benzotriazole (BtH) (1.14 g, 9.6 mmol) was added to
it and stirred at rt for 12 h. The volatiles were evaporated.
Chloroform (5 mL) was added to the residue and then purified by
silica gel column (20 cm × 2 cm) chromatography using chloroform
(100 mL) as an eluent to give 1-benzotriazol-1-yl-3,3,3-trifluoro-
2-methoxy-2-phenylpropan-1-one.
General Procedure for Synthesis of 2a-d: Benzotriazol-1-yl-
3,3,3-trifluoro-2-methoxy-2-phenylpropan-1-one (0.2 g, 0.6 mmol)
was added to amino acid, di-, or tripeptide (0.6 mmol) in CH3CN/
water (2:1, 15 mL). Triethyl amine (0.12 mL, 0.9 mmol) was added
dropwise to the above reaction mixture and stirred at rt for 12 h.
The volatiles were removed, and the residue was added to
ethylacetate (50 mL) and washed with 4 N HCl (10 mL); the organic
layer was separated and dried over Na2SO4, filtered, and evaporated
to give the products 2a-d.
(rac)-1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-
propan-1-one ((rac)-1): Yield 0.83 g (95%); white crystal; mp 99-
100 °C; 1H NMR δ 8.25 (d, J ) 8.2 Hz, 1H), 7.93 (d, J ) 8.1 Hz,
1H), 7.57 (t, J ) 7.7 Hz, 1H), 7.49-7.48 (m, 2H), 7.39 (t, J ) 7.7
Hz, 1H), 7.22-7.20 (m, 3H), 3.55 (2s, 3H); 13C NMR δ 165.7,
145.0, 133.1, 131.6, 131.2, 129.7, 128.6, 127.0, 126.4, 123.6 (q, J
) 289.1 Hz), 120.6, 114.6, 86.6 (q, J ) 26.7 Hz), 56.9, 56.8. Anal.
Calcd for C16H12F3N3O2: C, 57.32; H, 3.61; N, 12.53. Found: C,
57.43; H, 3.48; N, 12.5.
(R)-1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-
propan-1-one ((R)-1): Yield 0.83 g (95%); colorless oil; 1H NMR
δ 8.38 (d, J ) 8.2 Hz, 1H), 8.08 (d, J ) 8.1 Hz, 1H), 7.72 (t, J )
7.5 Hz, 1H), 7.66-7.46 (m, 2H), 7.54 (t, J ) 7.8 Hz, 1H), 7.42-
7.30 (m, 3H), 3.69 (s, 3H); 13C NMR δ 165.6, 144.9, 133.0, 131.5,
131.1, 129.6, 128.5, 126.9, 126.3, 126.3, 123.4 (q, J ) 290.7 Hz),
120.6, 114.5, 86.4 (q, J ) 26.7 Hz), 56.8, 56.8. Anal. Calcd for
C16H12F3N3O2: C, 57.32; H, 3.61; N, 12.53. Found: C, 57.24; H,
3.51; N, 12.21.
(S)-1-Benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenyl-
propan-1-one ((S)-1): Yield 0.83 g (95%); colorless oil; 1H NMR
δ 8.38 (d, J ) 8.2 Hz, 1H), 8.08 (d, J ) 8.2 Hz, 1H), 7.72 (t, J )
8.2 Hz, 1H), 7.66-7.58 (m, 2H), 7.54 (t, J ) 8.1 Hz, 1H), 7.40-
7.30 (m, 3H), 3.69 (s, 3H); 13C NMR δ 165.7, 145.0, 133.1, 131.6,
131.3, 130.7, 129.8, 129.1, 128.6, 127.0, 126.5, 123.4 (q, J ) 290.7
Hz), 120.7, 114.7, 86.4 (q, J ) 26.7 Hz), 57.0, 56.9. Anal. Calcd
for C16H12F3N3O2: C, 57.32; H, 3.61; N, 12.53. Found: C, 57.08;
H, 3.54; N, 12.37.
(R)-3-Phenyl-2-((rac)-3,3,3-trifluoro-2-methoxy-2-phenylpro-
pionylamino)propionic Acid ((R,R)- and (S,R)-2a): Yield 0.22 g
1
(96%); colorless oil; H NMR δ (1:1 mixture of diastereomers)
7.54-7.46 (m, 1H), 7.44-7.28 (m, 5H), 7.24-7.14 (m, 3H), 7.05
(d, J ) 8.5 Hz, 1H), 6.96 (2d, J ) 7.4 Hz, 1H), 5.01 (ddd, J ) 8.2,
7.4, 5.2 Hz, 1H), 4.94 (ddd, J ) 8.2, 7.4, 5.2 Hz, 1H), 3.39 (2s,
1.5H), 3.28 (2dd, J ) 14.3, 5.5 Hz, 1H), 3.19 (s, 1.5H), 3.08 (2dd,
J ) 14.1, 7.4 Hz, 1H); 13C NMR δ 175.8, 166.7, 166.6, 135.4,
135.4, 132.5, 132.0, 129.8, 129.7, 129.5, 129.4, 129.0, 128.9, 128.8,
128.8, 128.1, 127.6, 127.6, 127.5, 55.4, 55.0, 53.1, 52.8, 37.6, 37.4.
4270 J. Org. Chem., Vol. 72, No. 11, 2007

Anal. Calcd for C19H18F3NO4: C, 59.84; H, 4.76; N, 3.67. Found:
C, 59.72; H, 4.85; N, 3.73.
g (97%); white crystal; mp 84-86 °C; 1H NMR δ 7.78 (br s, 1H),
7.54-7.42 (m, 2H), 7.40-7.30 (m, 3H), 7.30-7.16 (m, 3H), 7.16-
7.06 (m, 2H), 6.87 (br s, 2H), 4.75 (dd, J ) 12.6, 6.9 Hz, 1H),
4.09 (dd, J ) 16.8, 6.0 Hz, 1H), 3.84 (dd, J ) 16.6, 4.9 Hz, 1H),
3.31 (s, 3H), 3.08 (dd, J ) 13.9, 4.9 Hz, 1H), 2.82 (dd, J ) 13.9,
7.0 Hz, 1H); 13C NMR δ 174.2, 168.6, 167.8, 136.0, 132.0, 129.9,
129.5, 128.9, 128.8, 128.0, 127.4, 123.9 (q, J ) 290.9 Hz), 84.3
(q, J ) 26.9 Hz), 55.2, 53.7, 42.8, 37.5. Anal. Calcd for
C21H21F3N2O5: C, 57.53; H, 4.83; N, 6.39. Found: C, 57.21; H,
4.92; N, 6.21.
(R)-3-Phenyl-2-((R)-3,3,3-trifluoro-2-methoxy-2-phenylpro-
pionylamino)propionic Acid ((R,R)-2a): Yield 0.22 g (96%); white
crystal; mp 110-112 °C; 1H NMR δ 8.79 (s, 1H), 7.54-7.44 (m,
2H), 7.44-7.23 (m, 7H), 7.22-7.12 (m, 2H), 4.93 (ddd, J ) 7.8,
7.7, 5.2 Hz, 1H), 3.28 (dd, J ) 14.1, 5.3 Hz, 1H), 3.18 (s, 3H),
3.14 (dd, J ) 14.1, 7.4 Hz, 1H); 13C NMR δ 175.9, 166.7, 135.4,
131.9, 129.8, 129.4, 129.0, 128.8, 128.6, 128.1, 127.9, 127.6, 123.8
(q, J ) 290.3 Hz), 84.2 (q, J ) 26.3 Hz), 55.0, 55.0, 53.1, 37.4;
19F NMR δ -69.37 (s, 3F). Anal. Calcd for C19H18F3NO4: C, 59.84;
H, 4.76; N, 3.67. Found: C, 59.46; H, 5.19; N, 3.54.
(R)-3-Phenyl-2-((S)-3,3,3-trifluoro-2-methoxy-2-phenylpropio-
nylamino)propionic Acid ((S,R)-2a): Yield 0.22 g (96%); white
crystal; mp 107-108 °C; 1H NMR δ 10.14 (s, 1H), 7.46-7.28 (m,
6H), 7.24-7.10 (m, 3H), 6.97 (2d, J ) 7.7 Hz, 1H), 5.03 (ddd, J
) 7.8, 7.7, 5.2 Hz, 1H), 3.38 (2s, 3H), 3.24 (dd, J ) 14.1, 5.2 Hz,
1H), 3.06 (dd, J ) 14.1, 7.4 Hz, 1H); 13C NMR δ 175.6, 166.7,
135.4, 132.4, 129.7, 129.4, 128.8, 128.7, 127.6, 127.4, 126.4, 123.7
(q, J ) 290.3 Hz), 115.1, 84.0 (q, J ) 26.3 Hz), 55.3, 52.9, 37.6;
19F NMR δ -69.31 (s, 3F). Anal. Calcd for C19H18F3NO4: C, 59.84;
H, 4.76; N, 3.67. Found: C, 59.57; H, 4.89; N, 3.59.
(R)-3-(1H-Indol-3-yl)-2-((R)-3,3,3-trifluoro-2-methoxy-2-phe-
nylpropionylamino)propionic Acid ((R,R)-2b): Yield 0.25 g
(98%); white crystal; mp 78-80 °C; 1H NMR δ 8.30 (s, 1H), 7.80-
7.52 (m, 1H), 7.52-7.27 (m, 8H), 7.23 (t, J ) 7.6 Hz, 1H), 7.07
(t, J ) 7.7 Hz, 1H), 6.80 (d, J ) 2.2 Hz, 1H), 5.09 (ddd, J ) 8.2,
6.2, 3.4 Hz, 1H), 3.37 (t, J ) 5.8 Hz, 2H), 3.32 (s, 3H); 13C NMR
δ 176.2, 167.1, 136.3, 132.5, 129.7, 128.7, 127.6, 127.5, 123.5,
122.4, 120.0, 118.4, 11.6, 109.1, 84.0 (q, J ) 26.3 Hz), 55.2, 53.0,
27.5. Anal. Calcd for C21H19F3N2O4: C, 60.00; H, 4.56; N, 6.66.
Found: C, 59.65; H, 4.48; N, 6.77.
(S)-3-Phenyl-2-{(S)-3-phenyl-2-[2-((R)-3,3,3-trifluoro-2-meth-
oxy-2-phenylpropionylamino)acetylamino]propionylamino}-
propionic Acid ((R,S,S)-2d): Yield 0.16 g (91%); white crystal;
1
mp 169-170 °C; H NMR (DMSO-d6) δ 8.45 (d, J ) 7.8 Hz,
1H), 8.40 (t, J ) 5.9 Hz, 1H), 8.08 (d, J ) 8.4 Hz, 1H), 7.56-7.36
(m, 6H), 7.32-7.12 (m, 9H), 4.58 (ddd, J ) 8.5, 8.9, 4.4 Hz, 1H),
4.44 (ddd, J ) 8.2, 8.2, 5.4 Hz, 1H), 3.82 (dd, J ) 16.5, 6.2 Hz,
1H), 3.61 (dd, J ) 16.5, 5.8 Hz, 1H), 3.49 (s, 1H), 3.42 (s, 3H),
3.12-2.88 (m, 4H), 2.71 (dd, J ) 13.9, 9.3 Hz, 1H); 13C NMR
(DMSO-d6) δ 172.8, 171.1, 167.8, 165.7, 137.6, 137.4, 133.1, 129.4,
129.3, 129.2, 128.3, 128.2, 128.0, 127.5, 126.5, 126.3, 125.8, 121.9,
83.5 (q, J ) 24.6 Hz), 55.0, 53.5. Anal. Calcd for C30H30F3N3O6:
C, 61.53; H, 5.16; N, 7.18. Found: C, 61.14; H, 5.55; N, 6.87.
Acknowledgment. We thank William Lewis for assistance
with the X-ray crystallography.
Supporting Information Available: Spectral data for new
compounds and details for the crystal structure of (rac)-1. This ma-
terial is available free of charge via the Internet at http://pubs.acs.org.
(R)-3-Phenyl-2-[2-((R)-3,3,3-trifluoro-2-methoxy-2-phenylpro-
pionylamino)acetylamino]propionic Acid ((R,R)-2c): Yield 0.13
JO070278A
J. Org. Chem, Vol. 72, No. 11, 2007 4271