Eur. J. Org. Chem. 2012 WILEY-VCH Verlag GmbH & Co.

KGaA, 69451 Weinheim, 2012 ISSN 1434193X

SUPPORTING INFORMATION

DOI: 10.1002/ejoc.201200722
Title: Direct CH Alkylation of Naphthoquinones with Amino Acids Through a Revisited KochiAnderson Radical
Decarboxylation: Trends in Reactivity and Applications
Author(s): Guillaume Naturale, Marc Lamblin, Claude Commandeur, Franois-Xavier Felpin, J ean Dessolin*

General remarks. All commercial solvents and reagents were used as received from the Aldrich
Chemical Company, Fischer Scientific Ltd, Alfa Aesar Company or TCI Europe companies. Silica gel
(40-63 m) used in flash column chromatography was obtained from Merck. Amino acids are of L
configuration unless otherwise stated. TLC analysis was performed on aluminium-backed plates (Merck)
coated with 0.2 mm silica with UV indicator 60
F254
.visualized with a Spectroline UV
254
lamp, and stained
with a basic solution of KMnO
4
or Ninhydrin. Solvent systems associated with R
f
values and flash
column chromatography are reported as percent by volume values. Mass spectra were performed by the
CESAMO (Bordeaux, France) on a QStar Elite mass spectrometer (Applied Biosystems). The instrument
is equipped with an ESI source and spectra were recorded in the positive mode. The electrospray needle
was maintained at 5000 V and operated at room temperature. Samples were introduced by injection
through a 20 L sample loop into a 4.5 mL/min flow of methanol from the LC pump.
1
H and
13
C NMR,
recorded at 300 MHz and 75 MHz, respectively, were performed on a Brucker Advance 300 spectrometer.
Proton chemical shifts were internally referenced to the residual proton resonance in CDCl
3
(o 7.26 ppm),
CD
3
OD (o 3.31 ppm), [D
6
]Acetone (o 2.05 ppm) or DMSO (o 2.54 ppm). Carbon chemical shifts were
internally referenced to the deuterated solvent signals in CDCl
3
(o 77.2 ppm), CD
3
OD (o 49.0 ppm)
[D
6
]Acetone (o 206.3, 29.8 ppm) or DMSO (o 40.45 ppm). FT-IR spectra were recorded on a Bruker
IRFT IFS55 spectrometer with samples loaded as neat films on ZnSe plates. Melting points (mp) were
determined with a melting point apparatus with a temperature gradient of 1C/min and are not corrected.


Amino acid Protecting group
Ac TFA Troc Boc
Glycine AA1a AA2a AA3a c.a.
|-alanine AA1b AA2b AA3b c.a.
-aminobutyric acid AA1c AA2c AA3c AA4c
Alanine AA1d AA2d AA3d c.a.
Phenylalanine AA1e AA2e AA3e c.a.
3-amino-2-methylpropanoic acid AA1f AA2f AA3f AA4f
Table 6. Protected amino acids numerotation

General procedure C for the synthesis of N-acetyl protected amino acids (AA1a-AA1f). To a
solution of the amino acid (1 equiv., 1.2 M) in MeOH was added acetic anhydride (2.7 equiv.). The
reaction mixture was refluxed for 6 h and then cooled to room temperature and all the volatiles were
removed under reduced pressure. The resulting colorless oil was kept overnight at -18C. Room
temperature warming allowed the crystallization of the chromatographically and spectroscopically pure
product.

General procedure D for the synthesis of N-trifluoroacetyl protected amino acids (AA2a-AA2f).
Triethylamine (1 equiv.) was added to a solution of amino acid (1 equiv., 2 M) in MeOH. After 5 min,
ethyl trifluoroacetate (1.25 equiv.) was added and the reaction was allowed to stir for 24 h. The solvent
was removed under reduced pressure and the remaining residue was dissolved in H
2
O and acidified with
concentrated HCl. After stirring for 15 min, the mixture was extracted with ethyl acetate and the
combined organic layer was washed with brine, dried over MgSO
4
, filtered and concentrated by rotary
evaporation. The resulting colorless oil was kept overnight at -18C. Room temperature warming allowed
the crystallization of the chromatographically and spectroscopically pure product.

General procedure E for the synthesis of N-trichloroethoxycarbonyl protected amino acids (AA3a-
AA3f). TrocCl (1.2 equiv.) was added to a 0C solution of glycine (1 equiv., 0.8 M) in aqueous 2 M NaOH.
The resulting solution was maintained at 0C for 1 h, at room temperature for 1.5 h and then diluted with
H
2
O and Et
2
O. The layers were separated, the aqueous layer was extracted with Et
2
O and the combined
organic extracts were discarded. The aqueous layer was acidified with 1 M HCl and extracted with ethyl
acetate. The combined organic layers were dried over Na
2
SO
4
and concentrated under reduced pressure.
The resulting colorless oil was kept overnight at -18C. Room temperature warming allowed the
crystallization of the chromatographically and spectroscopically pure product.

General procedure F for the synthesis of N-tert-butyloxycarbonyl protected amino acids (AA4c and
AA4f). To a solution of amino acid (1 equiv., 0.3 M) in 1 M NaOH/iPrOH (4:3) was added Boc
2
O (1
equiv.). The reaction mixture was stirred at room temperature for 2 h and then washed with petroleum
ether, acidified to pH 3.0 with 2 N H
2
SO
4
solution and finally extracted with chloroform. The organic
layer was dried over anhydrous Na
2
SO
4
and evaporated under reduced pressure. Purification was
performed by recrystallization from hexanes/chloroform to yield chromatographically and
spectroscopically pure product.

2-Acetamidoacetic acid (AA1a). This compound was prepared according to the general procedure C
starting from glycine (900 mg, 12 mmol) and acetic anhydride (3.06 mL, 32.4 mmol). The pure
compound was obtained as a colorless crystalline solid (1.39 g, 11.9 mmol, quantitative). The
spectroscopic data were identical to those reported in the literature.
[1]

1
H NMR (300 MHz, DMSO-d6) o
8.16 (bt, J = 5.3 Hz, 1H), 3.72 (d, J = 5.9 Hz,), 1.85 (s, 3H).

2-(2,2,2-Trifluoroacetamido)acetic acid (AA2a). This compound was prepared according to the general
procedure D starting from glycine (1.14 g, 15.4 mmol), triethylamine (2.15 mL, 15.4 mmol) and ethyl
trifluoroacetate (2.3 mL, 19.3 mmol). The pure compound was obtained as a colorless crystalline solid
(1.43 g, 8.4 mmol, 54%). The spectroscopic data were identical to those reported in the literature.
[2]

1
H
NMR (300 MHz, [D
6
] Acetone) o 8.76 (s, 1H), 4.12 (d, J = 6.0 Hz, 2H).

2-((2,2,2-Trichloroethoxy)carbonylamino)acetic acid (AA3a). This compound was prepared according
to the general procedure E starting from TrocCl (2.48 mL, 18 mmol) and glycine (1.11 g, 15 mmol). The
pure compound was obtained as a colorless crystalline solid (3.36 g, 13.4 mmol, 89%). mp 123-124C.
1
H
NMR (300 MHz, [D
6
] Acetone) o 7.06 (bs, 1H), 4.82 (s, 2H), 3.96 (d, J = 6.2 Hz, 2H).
13
C NMR (75
MHz, [D
6
] Acetone) o 170.3, 155.0, 96.0, 74.1, 42.1.

3-Acetamidopropanoic acid (AA1b). This compound was prepared according to the general procedure
C starting from |-alanine (2.14 g, 24 mmol) and acetic anhydride (6.12 mL, 65 mmol). The pure
compound was obtained as a colorless crystalline solid (3.17 g, 24 mmol, quantitative). mp 77-79C.
1
H
NMR (300 MHz, CD
3
OD) o 3.42 (t, J = 6.7 Hz, 2H), 2.51 (t, J = 6.7 Hz, 2H), 1.94 (s, 3H).
13
C NMR (75
MHz, CD
3
OD) o 174.2, 172.0, 35.1, 33.4, 21.1.

3-(2,2,2-Trifluoroacetamido)propanoic acid (AA2b). This compound was prepared according to the
general procedure D starting from |-alanine (1.37 g, 15.4 mmol), triethylamine (2.15 mL, 15.4 mmol)
and ethyl trifluoroacetate (2.3 mL, 19.3 mmol). The pure compound was obtained as a colorless
crystalline solid (2.35 g, 12.7 mmol, 82%). The spectroscopic data were identical to those reported in the
literature.
[3]

1
H NMR (300 MHz, CD
3
OD) o 3.55 (t, J = 6.9 Hz, 2H), 2.60 (t, J = 6.9 Hz, 2H).

3-((2,2,2-Trichloroethoxy)carbonylamino)propanoic acid (AA3b). This compound was prepared
according to the general procedure E starting from TrocCl (2.48 mL, 18 mmol) and |-alanine (1.34 g, 15
mmol). The pure compound was obtained as a colorless crystalline solid (3.19 g, 12.1 mmol, 80%). mp

[
1
] M. A. Muhammad, S. Rahat, K. M. Khan, Z.Ullah, M. I. Choudhary, S. Murad, Z. Ismail, A. Rahman, A.
Ahmad, Bioorg. Med. Chem. 2004, 12, 2049-2057.
[
2
] R. B. C. Jagt, R. F. Gomez-Biagi, M. Nitz, Angew. Chem., Int. Ed. 2009, 48, 1995-1997.
[
3
] M. S. Cherevin, Z. P. Zubreichuk, L. A. Popova, T. G. Gulevich, V. A. Knizhnikov, Russ. J. Gen. Chem.
2007, 77, 1576-1579.
83-84C.
1
H NMR (300 MHz, CD
3
OD) o 7.44 (bs, 1H), 4.88 (s, 2H), 3.41 (dt, J = 6.7, 4.3 Hz, 2H), 2.54
(t, J = 6.9 Hz, 2H).
13
C NMR (75 MHz, CD
3
OD) o 173.8, 155.4, 95.8, 74.0, 36.6, 33.5.

4-Acetamidobutanoic acid (AA1c). This compound was prepared according to the general procedure C
starting from -aminobutyric acid (1.03 g, 10 mmol) and acetic anhydride (2.55 mL, 27 mmol). The pure
compound was obtained as a colorless crystalline solid (1.09 g, 7.5 mmol, 75%). The spectroscopic data
were identical to those reported in the literature.
[4]

1
H NMR (300 MHz, CD
3
OD) o 3.22 (t, J = 6.9 Hz,
2H), 2.34 (t, J = 7.4 Hz, 2H), 1.94 (s, 3H), 1.80 (p, J = 7.2 Hz, 2H).

4-(2,2,2-Trifluoroacetamido)butanoic acid (AA2c). This compound was prepared according to the
general procedure D starting from -aminobutyric acid (2.06 g, 20 mmol), triethylamine (2.79 mL, 20
mmol) and ethyl trifluoroacetate (3 mL, 25 mmol). The pure compound was obtained as a colorless
crystalline solid (3.53 g, 17.7 mmol, 89%). The spectroscopic data were identical to those reported in the
literature.
[5]

1
H NMR (300 MHz, CD
3
OD) o 5.08 (bs, 1H), 3.35 (t, J = 6.9 Hz, 2H), 2.36 (t, J = 7.3 Hz,
2H), 1.86 (p, J = 7.2 Hz, 2H).

4-((2,2,2-Trichloroethoxy)carbonylamino)butanoic acid (AA3c). This compound was prepared
according to the general procedure E starting from TrocCl (3.3 mL, 24 mmol) and -aminobutyric acid
(2.06 g, 20 mmol). The pure compound was obtained as a colorless crystalline solid (4.65 g, 16.7 mmol,
83%). mp 41-42C.
1
H NMR (300 MHz, CD
3
OD) o 7.44 (bs, 1H), 4.97 (bs, 1H), 4.78 (s, 2H), 3.27 3.16
(m, 2H), 2.36 (t, J = 7.4 Hz, 2H), 1.92 1.74 (m, 2H).
13
C NMR (75 MHz, CD
3
OD) o 175.5, 155.6, 95.9,
74.0, 39.9, 30.6 , 24.7.

4-(tert-Butoxycarbonylamino)butanoic acid (AA4c). This compound was prepared according to the
general procedure F starting from -aminobutyric acid (2.58 g, 25 mmol) and Boc
2
O (5.46 mg, 25 mmol).
The pure compound was obtained as a colorless crystalline solid (5.02 g, 24.7 mmol, 99%). The
spectroscopic data were identical to those reported in the literature.
[6]

1
H NMR (300 MHz, CD
3
OD) o
4.92 (bs, 1H), 3.09 (t, J = 6.9 Hz, 2H), 2.33 (t, J = 7.4 Hz, 2H), 1.76 (p, J = 7.2 Hz, 2H), 1.45 (s, 9H).

2-Acetamidopropanoic acid (AA1d). This compound was prepared according to the general procedure
C starting from D,L-alanine (2.14 g, 24 mmol) and acetic anhydride (6.14 mL, 65 mmol). The pure

[
4
] J. Liu, T. Xie, X.-L. Wei, H. Yang, C.-H. Yang, J.-Y. Liang, Zhongguo Tianran Yaowu 2004, 2, 276-279.
[
5
] C.-Y. Zhou, W.-Y. Yu, P. W. H. Chan, C.-M. Che, J. Org. Chem. 2004, 69, 7072-7082.
[
6
] E. Guenin, M. Monteil, N. Bouchemal, T. Prange, M. Lecouvey, Eur. J. Org. Chem. 2007, 3380-3391.
compound was obtained as a colorless crystalline solid (2.30 g, 17.5 mmol, 73%). mp 136-137C.
1
H
NMR (300 MHz, CD
3
OD) o 4.38 (q, J = 7.3 Hz, 1H), 1.99 (s, 3H), 1.40 (d, J = 7.3 Hz, 3H).
13
C NMR (75
MHz, CD
3
OD) o 174.7, 171.7, 48.0, 20.9, 16.2.

2-(2,2,2-Trifluoroacetamido)propanoic acid (AA2d). This compound was prepared according to the
general procedure D starting from D,L-alanine (1.37 g, 15.4 mmol), triethylamine (2.15 mL, 15.4 mmol)
and ethyl trifluoroacetate (2.3 mL, 19.3 mmol). The pure compound was obtained as a colorless
crystalline solid (1.93 g, 10.4 mmol, 68%). mp 119-120C.
1
H NMR (300 MHz, CD
3
OD) o 4.46 (q, J =
7.3 Hz, 1H), 1.48 (d, J = 7.4 Hz, 3H).
13
C NMR (75 MHz, CD
3
OD) o 174.1, 157.7, 157.2, 156.7, 156.2,
121.6, 117.7, 113.9, 110.1, 51.3, 18.5.

2-((2,2,2-Trichloroethoxy)carbonylamino)propanoic acid (AA3d). This compound was prepared
according to the general procedure E starting from TrocCl (2.48 mL, 18 mmol) and D,L-alanine (1.34 g,
15 mmol). The pure compound was obtained as a colorless crystalline solid (3.13 g, 11.8 mmol, 79%).
mp 130-131C.
1
H NMR (300 MHz, CD
3
OD) o 7.74 (bd, J = 7.2 Hz, 1H), 4.79 (q, J = 12.2 Hz, 2H), 4.22
(qt, J = 7.3 and 3.7 Hz, 1H), 1.43 (d, J = 7.3 Hz, 3H).
13
C NMR (75 MHz, CD
3
OD) o 174.7, 155.1, 95.6,
74.2, 49.6, 16.3.
2-Acetamido-3-phenylpropanoic acid (AA1e). This compound was prepared according to the general
procedure C starting from D,L-phenylalanine (3.96 g, 24 mmol) and acetic anhydride (6.14 mL, 65 mmol).
The pure compound was obtained as a colorless crystalline solid (4.25 g, 20.5 mmol, 86%). The
spectroscopic data were identical to those reported in the literature.
[7]

1
H NMR (300 MHz, CD
3
OD) o
7.38 7.13 (m, 5H), 4.72 4.60 (m, 1H), 3.21 (dd, J = 13.9, 5.1 Hz, 1H), 2.95 (dd, J = 13.9, 9.1 Hz, 1H),
1.91 (s, 3H,).

3-Phenyl-2-(2,2,2-trifluoroacetamido)propanoic acid (AA2e). This compound was prepared according
to the general procedure D starting from D,L-phenylalanine (2.48 g, 15 mmol), triethylamine (2.1 mL, 15
mmol) and ethyl trifluoroacetate (2.2 mL, 18.8 mmol). The pure compound was obtained as a colorless
crystalline solid (3.74 g, 14.3 mmol, 95%). mp 126-128C.
1
H NMR (300 MHz, CD
3
OD) o 7.39 7.10
(m, 5H), 4.69 (dd, J = 10.0, 4.6 Hz, 1H), 3.39 3.33 (m, 1H), 3.03 (dd, J = 14.0, 10.0 Hz, 1H).
13
C NMR
(75 MHz, CD
3
OD) o 172.3, 158.1, 157.6, 157.1, 156.6, 136.8, 128.8, 128.1, 126.6, 121.6, 117.8, 114.1,
110.3, 54.4, 36.4.


[
7
] B. Zhu, X. Jiang, Synlett 2006, 2795-2798.
3-Phenyl-2-((2,2,2-trichloroethoxy)carbonylamino)propanoic acid (AA3e). This compound was
prepared according E to the general procedure starting from TrocCl (4.3 mL, 31 mmol) and D,L-
phenylalanine (4.29 g, 26 mmol). The pure compound was obtained as a colorless crystalline solid (7.84 g,
23 mmol, 89%). mp 118-119C.
1
H NMR (300 MHz, CD
3
OD) o 7.56 (d, J = 8.4 Hz, 1H), 7.36 7.02 (m,
5H), 5.16 (bs, 1H), 4.69 (q, J = 12.2 Hz, 2H), 4.50 (td, J = 9.1, 4.9 Hz, 1H), 3.25 (dd, J = 14.0, 4.8 Hz,
1H), 2.97 (dd, J = 14.0, 9.5 Hz, 1H).
13
C NMR (75 MHz, CD
3
OD) o 173.4, 155.1, 137.0, 129.0, 128.1,
126.4, 95.6, 74.1, 55.6, 37.2.

3-Acetamido-2-methylpropanoic acid (AA1f). This compound was prepared according to the general
procedure C starting from D,L-3-amino-2-methylpropanoic acid (310 mg, 3 mmol) and acetic anhydride
(765 L, 8.1 mmol). The pure compound was obtained as a colorless crystalline solid (193 mg, 1.3 mmol,
44%). mp 80-82C.
1
H NMR (300 MHz, CD
3
OD) o 3.44 3.22 (m, 1H), 2.76 2.56 (m, 2H), 1.95 (s,
3H), 1.17 (d, J = 7.1 Hz, 3H).
13
C NMR (75 MHz, CD
3
OD) o 174.2, 171.9, 40.6, 38.9, 23.1, 15.0.

2-Methyl-3-(2,2,2-trifluoroacetamido)propanoic acid (AA2f). This compound was prepared according
to the general procedure D starting from D,L-3-amino-2-methylpropanoic acid (310 mg, 3 mmol),
triethylamine (418 L, 3 mmol) and ethyl trifluoroacetate (446 L, 3.75 mmol). The pure compound was
obtained as a colorless crystalline solid (481 mg, 2.4 mmol, 81%). mp 61-65C.
1
H NMR (300 MHz,
CD
3
OD) o 10.66 (bs, 1H), 8.37 (d, J = 40.7 Hz, 1H), 3.71 3.52 (m, 1H), 3.52 3.32 (m, 1H), 2.94
2.70 (m, 1H), 1.18 (d, J = 7.2 Hz, 3H).
13
C NMR (75 MHz, CD
3
OD) o 175.8, 157.8, 157.4, 156.9, 156.4,
121.8, 118.0, 114.2, 110.4, 42.0, 38.4, 14.0.

2-Methyl-3-((2,2,2-trichloroethoxy)carbonylamino)propanoic acid (AA3f). This compound was
prepared according to the general procedure E starting from TrocCl (496 L, 3.6 mmol) and D,L-3-amino-
2-methylpropanoic acid (310 mg, 3 mmol). The pure compound was obtained as a colorless crystalline
solid (566 mg, 2 mmol, 68%). mp 81-82C.
1
H NMR (300 MHz, [D
6
] Acetone) o 6.87 (bs, 1H), 4.80 (s,
2H), 3.56 3.38 (m, 1H), 3.38 3.22 (m, 1H), 2.83 2.67 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H).
13
C NMR
(75 MHz, [D
6
] Acetone) o 175.2, 154.7, 96.2, 73.9, 43.6, 39.2, 14.1.

3-(tert-Butoxycarbonylamino)-2-methylpropanoic acid (AA4f). This compound was prepared
according to the general procedure F starting from D,L-3-amino-2-methylpropanoic acid (310 mg, 3
mmol) and Boc
2
O (655 mg, 3 mmol). The pure compound was obtained as a colorless crystalline solid
(489 mg, 2.4 mmol, 80%). The spectroscopic data were identical to those reported in the literature.
[8]

1
H
NMR (300 MHz, [D
6
] Acetone) o 5.97 (bs, 1H), 3.39 3.25 (m, 1H), 3.24 3.09 (m, 1H), 2.74 2.60 (m,
1H), 1.41 (s, 9H), 1.15 (d, J = 7.1 Hz, 3H).

General procedure G, Synthesis of amino acid methyl ester hydrochlorides (AAMe1-). To a stirred
suspension of amino acid (1 equiv., 0.5 M) in methanol at -10C was slowly added thionyl chloride (1.2
equiv.). The reaction mixture was refluxed for 3 h then cooled down to room temperature. The solvent
was removed by rotary evaporation under reduced pressure to afford the chromatographically and
spectroscopically pure product.

General procedure H, Peptidic coupling of N-Boc protected chiral amino acids on methyl ester
hydrochlorides (PEP1-). To a solution of N-Boc protected chiral amino acid (1 equiv., 0.1 M) in DCM
were added methyl ester hydrochloride (1 equiv.), HOBt-0.8H
2
O (1.5 equiv.) and TEA (3 equiv.). The
reaction mixture was cooled to 0C before EDC-HCl (1.1 equiv.) was added in one part. The temperature
was allowed to reach r.t. overnight. The reaction mixture was then washed twice with 0.1 M NaOH
solution, then water, twice with 0.1 M HCl solution, water and finally brine. The organic layer was dried
over MgSO
4
and evaporated under reduced pressure to afford the chromatographically and
spectroscopically pure product.

General procedure I, Saponification of methyl esters (PEPOH1-). To a solution of N-Boc protected
methyl ester dipeptides (1 equiv., 0.5 M) in MeOH was added 2 M NaOH solution (3.2 equiv.). The
reaction mixture was allowed to stir for 20 h at room temperature. The solvent was then removed under
reduced pressure and the residue was taken with water and washed with diethyl ether. The pH of the
aqueous layer was adjusted to 2 using 1 M HCl solution and then extracted with ethyl acetate. The organic
layer was dried over MgSO
4
and evaporated under reduced pressure to afford the chromatographically
and spectroscopically pure product.

Methyl 2-aminoethanoate hydrochloride (AAMe1). This compound was prepared according to the
general procedure G starting from glycine (3 g, 40 mmol) and SOCl
2
(3.48 mL, 48 mmol). The pure
compound was obtained as a colorless crystalline solid (5.01 g, 40 mmol, quantitative). The spectroscopic

[
8
] R. Moumne, S. Lavielle, P. Karoyan, J. Org. Chem. 2006, 71, 3332-3334.
data were identical to those reported in the literature.
[9] 1
H NMR (300 MHz, CD
3
OD) o 4.21 (d, J = 6.3
Hz, 2H), 3.73 (s, 3H).

(S)-Methyl 2-(2-(tert-butoxycarbonylamino)propanamido)acetate (PEP1). This compound was
prepared according to the general procedure H starting from Boc-L-alanine (341 mg, 1.8 mmol), methyl
ester hydrochloride AAMe1 (226 mg, 1.8 mmol), HOBt-0.8 H
2
O (404 mg, 2.7 mmol), triethylamine (752
L, 5.4 mmol) and EDC-HCl (307 mg, 2 mmol). The pure compound was obtained as a colorless
crystalline solid (398 mg, 1.53 mmol, 85%). The spectroscopic data were identical to those reported in the
literature.
[10]

1
H NMR (300 MHz, CDCl
3
) o 6.82 (bs, 1H), 5.12 (bd, J = 7.4 Hz, 1H), 4.28 4.16 (m, 1H),
4.11 3.98 (m, 2H), 3.76 (s, 3H), 1.45 (s, 9H), 1.39 (d, J = 7.1 Hz, 3H).

(S)-2-(2-(tert-Butoxycarbonylamino)propanamido)acetic acid (PEPOH1). This compound was
prepared according to the general procedure I starting from N-Boc protected methyl ester dipeptide PEP1
(338 mg, 1.3 mmol) and 2 M NaOH solution (2.1 mL, 4.2 mmol). The pure compound was obtained as a
colorless crystalline solid (256 mg, 1 mmol, 80%). The spectroscopic data were identical to those
reported in the literature.
[11]

1
H NMR (300 MHz, CDCl
3
) o 7.98 (bs, 1H), 6.80 (bs, 1H), 5.15 (bd, J = 7.4
Hz, 1H), 4.26 4.14 (m, 1H), 4.15 3.97 (m, 2H), 1.43 (s, 9H), 1.38 (d, J = 7 Hz, 3H).

Methyl 3-aminopropanoate hydrochloride (AAMe2). This compound was prepared according to the
general procedure G starting from |-alanine (3.56 g, 40 mmol) and SOCl
2
(3.48 mL, 48 mmol). The pure
compound was obtained as a colorless crystalline solid (5.58 g, 40 mmol, quantitative). The spectroscopic
data were identical to those reported in the literature.
[12]

1
H NMR (300 MHz, CD
3
OD) o 3.76 (s, 3H), 3.25
(t, J = 6.5 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H).

(S)-Methyl 3-(2-(tert-butoxycarbonylamino)-3-phenylpropanamido)propanoate (PEP2). This
compound was prepared according to the general procedure H starting from Boc-L-phenylalanine (956
mg, 3.6 mmol), methyl ester hydrochloride AAMe2 (502 mg, 3.6 mmol), HOBt-0.8H
2
O (808 mg, 5.4
mmol), triethylamine (1.5 mL, 10.8 mmol) and EDC-HCl (614 mg, 4 mmol). The pure compound was
obtained as a colorless crystalline solid (945 mg, 2.7 mmol, 75%). The spectroscopic data were identical

[
9
] L. Gros, S. O. Lorente, C. Jimenez Jimenez, V. Yardley, L. Rattray, H. Wharton, S. Little, S. L. Croft, L. M.
Ruiz-Perez, D. Gonzalez-Pacanowska, I. H. Gilbert, J. Med. Chem. 2006, 49, 6094-6103.
[
10
] R. Dahiya, J. Iran. Chem. Soc. 2008, 5, 445-452.
[
11
] C. Hashimoto, K. Takeguchi, M. Kodomari, Synlett 2011, 1427-1430.
[
12
] F. J. Dekker, M. Ghizzoni, N. van der Meer, R. Wisastra, H. Haisma, J. Bioorg. Med. Chem. 2009, 17, 460-
466.
to those reported in the literature.
[13]

1
H NMR (300 MHz, CD
3
OD) o 7.38 7.12 (m, 5H), 4.31 4.15 (m,
1H), 3.67 (s, 3H), 3.52 3.35 (m, 2H), 3.06 (dd, J = 13.7, 6.2 Hz, 1H), 2.82 (dd, J = 13.7, 8.7 Hz, 1H),
2.53 2.41 (m, 2H), 1.38 (s, 9H).

(S)-3-(2-(tert-Butoxycarbonylamino)-3-phenylpropanamido)propanoic acid (PEPOH2). This
compound was prepared according to the general procedure I starting from N-Boc protected methyl ester
dipeptide PEP2 (416 mg, 1.2 mmol) and 2 M NaOH solution (1.9 mL, 3.8 mmol). The pure compound
was obtained as a colorless crystalline solid (345 mg, 1 mmol, 86%). The spectroscopic data were
identical to those reported in the literature.
[14]

1
H NMR (300 MHz, CD
3
OD) o 7.96 (bs, 1H), 7.36 7.14
(m, 5H), 6.69 (d, J = 7.9 Hz, 1H), 4.24 (bs, 1H), 3.51 3.35 (m, 2H), 3.07 (dd, J = 13.6, 6.0 Hz, 1H), 2.83
(dd, J = 13.6, 8.8 Hz, 1H), 2.49 2.38 (m, 2H), 1.38 (s, 9H).

Methyl 4-aminobutanoate hydrochloride (AAMe3). This compound was prepared according to the
general procedure G starting from -aminobutyric acid (4.12 g, 40 mmol) and SOCl
2
(3.48 mL, 48 mmol).
The pure compound was obtained as a colorless crystalline solid (5.96 g, 39 mmol, 97%). The
spectroscopic data were identical to those reported in the literature.
[12]

1
H NMR (300 MHz, CD
3
OD) o
3.72 (s, 3H), 3.05 (t, J = 7.2 Hz, 2H), 2.61 2.44 (m, 2H), 2.10 1.91 (m, 2H).

(S)-Methyl 4-(2-(tert-butoxycarbonylamino)-3-phenylpropanamido)butanoate (PEP3): This
compound was prepared according to the general procedure H starting from Boc-L-phenylalanine (478
mg, 1.8 mmol), methyl ester hydrochloride AAMe3 (276 mg, 1.8 mmol), HOBt-0.8H
2
O (404 mg, 2.7
mmol), triethylamine (752 L, 5.4 mmol) and EDC-HCl (307 mg, 2 mmol). The pure compound was
obtained as a colorless crystalline solid (540 mg, 1.5 mmol, 82%). mp 90-91C.
1
H NMR (300 MHz,
CD
3
OD) o 7.36 7.12 (m, 5H), 4.23 (t, J = 7.4 Hz, 1H), 3.67 (s, 3H), 3.28 3.08 (m, 2H), 3.04 (dd, J =
13.5, 6.7 Hz, 1H), 2.85 (dd, J = 13.5, 8.3 Hz, 1H), 2.24 (t, J = 7.5 Hz, 2H), 1.71 (p, J = 7.0 Hz, 2H), 1.39
(s, 9H).
13
C NMR (75 MHz, CD
3
OD) o 173.9, 172.9, 156.1, 137.1, 129.0, 128.0, 126.3, 79.2, 56.2, 50.6,
38.1, 38.0, 30.5, 27.2, 24.1.

(S)-4-(2-(tert-Butoxycarbonylamino)-3-phenylpropanamido)butanoic acid (PEPOH3): This
compound was prepared according to the general procedure I starting from N-Boc protected methyl ester
dipeptide PEP3 (942 mg, 2.6 mmol) and 2 M NaOH solution (4.3 mL, 8.6 mmol). The pure compound

[
13
] H. S. Iden, W. D. Lubell, Org. Lett. 2006, 8, 3425-3428.
[
14
] S. Guha, M. G. B. Drew, A. Banerjee, Org. Lett. 2007, 9, 1347-1350.
was obtained as a colorless crystalline solid (792 mg, 2.3 mmol, 88%). mp 124-126C.
1
H NMR (300
MHz, CD
3
OD) o 7.96 (bs, 1H), 7.36 7.14 (m, 5H), 6.65 (bd, J = 7.7 Hz, 1H), 4.24 (bt, J = 7.1 Hz, 1H),
3.28 3.12 (m, 2H), 3.05 (dd, J = 13.6, 6.6 Hz, 1H), 2.85 (dd, J = 13.6, 8.3 Hz, 1H), 2.22 (t, J = 7.4 Hz,
2H), 1.77 1.63 (m, 2H), 1.39 (s, 9H).
13
C NMR (75 MHz, CD
3
OD) o 173.7, 172.6, 156.1, 137.1,
128.9, 128.1, 126.3, 79.2, 56.3, 38.2, 38.1, 30.5, 27.4, 24.3.
O
O
N
H
O
O
10
Figure SI-1. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
O
11a
Figure SI-2. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
O CCl
3
11b
Figure SI-3. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
11c
Figure SI-4. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N CF
3
O
11d
Figure SI-5. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
Cl
Cl
Cl
O
12b
Figure SI-6. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
12c
Figure SI-7. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
CF
3
O
12d
Figure SI-8. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
O
13a
Figure SI-9. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
O
Cl
Cl
Cl
13b
Figure SI-10. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
13c
Figure SI-11. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
F
F
F
13d
Figure SI-12. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
Cl
Cl
Cl
O
14b
Figure SI-13. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
14c
Figure SI-14. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
F
O
F
F
14d
Figure SI-15. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in DMSO-d6
O
O
H
N O
Cl
Cl
Cl
O
15b
Figure SI-16. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
15c
Figure SI-17. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
F
O
F
F
15d
Figure SI-18. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
O
16a
Figure SI-19. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
O
Cl
Cl
Cl
16b
Figure SI-20. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
16c
Figure SI-21. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
F
F
F
16d
Figure SI-22. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
O
17a
Figure SI-23. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
O
HN
O
O
17aa
Figure SI-24. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
O
Cl
Cl
Cl
17b
Figure SI-25. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
O
Cl
Cl
Cl
HN
O
O
Cl
Cl
Cl
17bb
Figure SI-26. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
17c
Figure SI-27. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
17cc
N
H
O
HN
O
Figure SI-28. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N CF
3
O
17d
Figure SI-29. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
O
18a
Figure SI-30. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
O
Cl
Cl
Cl
18b
Figure SI-31. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
O
Cl
Cl
Cl
NH
O O
Cl
Cl
Cl
18bb
Figure SI-32. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
18c
Figure SI-33. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
CF
3
O
18d
Figure SI-34. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in [D6] Acetone
O
O
N
H
CF
3
O
NH
CF
3
O
18dd
Figure SI-35. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD and [D6] Acetone
O
O
H
N O
O
19a
Figure SI-36. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
O
HN
O
O
19aa
Figure SI-37. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
O
Cl
Cl
Cl
19b
Figure SI-38. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
O
Cl
Cl
Cl
HN
O
O
Cl
Cl
Cl
19bb
Figure SI-39. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
19c
Figure SI-40. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
HN O
19cc
Figure SI-41. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
F
F
F
19d
Figure SI-42. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in [D6] Acetone
O
O
H
N
O
F
F
F
HN
O
F
F
F
19dd
Figure SI-43. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in [D6] Acetone
O
O
H
N O
O
20a
Figure SI-44. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
Cl
O
Cl
Cl
20b
Figure SI-45. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
20c
Figure SI-46. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
F
O
F
F
20d
Figure SI-47. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
F
O
F
F
HN
O
F
F
F
20dd
Figure SI-48. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
O
21a
Figure SI-49. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N O
Cl
O
Cl
Cl
21b
Figure SI-50. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
21c
Figure SI-51. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
F
O
F
F
21d
Figure SI-52. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
F
O
F
F
N
H
O
F
F
F
21dd
Figure SI-53. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
O
22a
Figure SI-54. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
O
NH
O O
22aa
Figure SI-55. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
O
Cl
Cl
Cl
22b
Figure SI-56. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
22c
Figure SI-57. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
F
F
F
22d
Figure SI-58. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
F
F
F
NH
O
F
F
F
22dd
Figure SI-59. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
O
O
H
N
O
F
F
F
N
H
O
O
23a
Figure SI-60. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
N
H
O
O
O
Cl
Cl
Cl
23b
Figure SI-61. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
H
N O
O
F
F
F
24a
Figure SI-62. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
H
N O
O
O
Cl
Cl
Cl
24b
Figure SI-63. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
N
H
O
O
O
25
Figure SI-64. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
H
N O
O
O
26
Figure SI-65. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
N
27
Figure SI-66. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
N
28
Figure SI-67. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
N
H
O
O
O
29
Figure SI-68. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
N
H
O
O
O
30
Figure SI-69. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in DMSO-d6
O
O
N
H
O
H
N O
O
31
Figure SI-70. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in DMSO-d6
O
O
N
H
O
H
N O
O
32
Figure SI-71. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
N
H
H
N
O
O
O
O
33
Figure SI-72. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
H
N
O
H
N
O
O
N
H
O
O
34
Figure SI-73. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
N
H
O
O
O
H
N O
O
35
Figure SI-74. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O
O
N
H
O
O
H
N
N
H
O
O
O
36
Figure SI-75. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
HO
H
N
O
O
AA1a
Figure SI-76. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in DMSO-d6
HO
O
H
N
O
F
F
F
AA2a
Figure SI-77. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in [D6] Acetone
HO
O
H
N O
O
Cl
Cl
Cl
AA3a
Figure SI-78. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in [D6] Acetone
HO N
H
O O
AA1b
Figure SI-79. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
O
N
H
O
F
F
F
AA2b
Figure SI-80. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
O
N
H
O
Cl
Cl
Cl
O
AA3b
Figure SI-81. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
O
H
N
O
AA1c
Figure SI-82. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
O
N
H
O
F
F
F
AA2c
Figure SI-83. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in [D6] Acetone
HO
O
H
N O
Cl
Cl
Cl
O
AA3c
Figure SI-84. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
H
N O
O
O
AA4c
Figure SI-85. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
O
H
N
O
AA1d
Figure SI-86. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
O
H
N
O
F
F
F
AA2d
Figure SI-87. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
O
H
N O
O
Cl
Cl
Cl
AA3d
Figure SI-88. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
O
H
N
O
AA1e
Figure SI-89. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
O
H
N
O
F
F
F
AA2e
Figure SI-90. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
O
H
N O
O
Cl
Cl
Cl
AA3e
Figure SI-91. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
HO
O
N
H
O
AA1f
Figure SI-92. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
HO
O
N
H
O
F
F
F
AA2f
Figure SI-93. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in [D6] Acetone
HO
O
N
H
O
Cl
Cl
Cl
O
AA3f
Figure SI-94. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in [D6] Acetone
HO N
H
O
O O
AA4f
Figure SI-95. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in [D6] Acetone
O
NH
2
O
HCl
AAMe1
Figure SI-96. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
O
H
N
O
N
H
O
O O
PEP1
Figure SI-97. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
HO
H
N
O
N
H
O
O O
PEPOH1
Figure SI-98. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
O NH
2
O
HCl
AAMe2
Figure SI-99. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
N
H
O
H
N O
O
O
O
PEP2
Figure SI-100. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
HO
H
N
O
N
H
O
O
O
PEPOH2
Figure SI-101. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
O
O
HCl NH
2
AAMe3
Figure SI-102. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD
O
O
H
N
O
N
H
O
O
PEP3
Figure SI-103. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in CDCl
3
HO
H
N
O
N
H
O
O
O
PEPOH3
Figure SI-104. 300 MHz
1
H and 75 MHz
13
C{
1
H} NMR in MeOD