8/11/2019 Acylation of a-Amino Acids MeOH.pdf
1/115
Eur. J. Org. Chem.2012 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2012 ISSN 1434193X
SUPPORTING INFORMATION
DOI:10.1002/ejoc.201200722Title: Direct CH Alkylation of Naphthoquinones with Amino Acids Through a Revisited KochiAnderson RadicalDecarboxylation: Trends in Reactivity and Applications
Author(s): Guillaume Naturale, Marc Lamblin, Claude Commandeur, Franois-Xavier Felpin, Jean Dessolin*
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
2/115
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 60F254.visualized with a Spectroline UV254lamp, and stained
with a basic solution of KMnO4 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. 1H and 13C 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 CDCl3( 7.26 ppm),
CD3OD (3.31 ppm), [D 6]Acetone (2.05 ppm) or DMSO ( 2.54 ppm). Carbon chemical shifts were
internally referenced to the deuterated solvent signals in CDCl3 ( 77.2 ppm), CD 3OD ( 49.0 ppm)
[D6]Acetone ( 206.3, 29.8 ppm) or DMSO ( 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
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
3/115
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 H2O 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 MgSO4, 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
H2O and Et2O. The layers were separated, the aqueous layer was extracted with Et2O and the combined
organic extracts were discarded. The aqueous layer was acidified with 1 MHCl and extracted with ethyl
acetate. The combined organic layers were dried over Na2SO4and 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 MNaOH/ iPrOH (4:3) was added Boc2O (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 2SO4 solution and finally extracted with chloroform. The organic
layer was dried over anhydrous Na2SO4 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
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
4/115
spectroscopic data were identical to those reported in the literature. [1] 1H NMR (300 MHz, DMSO-d6)
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] 1H
NMR (300 MHz, [D6] Acetone) 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. 1H
NMR (300 MHz, [D6] Acetone) 7.06 (bs, 1H), 4.82 (s, 2H), 3.96 (d, J= 6.2 Hz, 2H).13C NMR (75
MHz, [D6] Acetone) 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. 1H
NMR (300 MHz, CD3OD) 3.42 (t, J= 6.7 Hz, 2H), 2.51 (t, J= 6.7 Hz, 2H), 1.94 (s, 3H).13C NMR (75
MHz, CD3OD) 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] 1H NMR (300 MHz, CD3OD) 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.
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
5/115
83-84C. 1H NMR (300 MHz, CD3OD) 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). 13C NMR (75 MHz, CD3OD)
4-Acetamidobutanoic acid (AA1c).This compound was prepared according to the general procedure Cstarting 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] 1H NMR (300 MHz, CD3OD) 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, 20mmol) 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] 1H NMR (300 MHz, CD3OD) 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. 1H NMR (300 MHz, CD3OD) 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). 13C NMR (75 MHz, CD3OD) 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 Boc2O (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] 1H NMR (300 MHz, CD3OD)
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.
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
6/115
compound was obtained as a colorless crystalline solid (2.30 g, 17.5 mmol, 73%). mp 136-137C. 1H
NMR (300 MHz, CD3OD) 4.38 (q, J= 7.3 Hz, 1H), 1.99 (s, 3H), 1.40 (d, J= 7.3 Hz, 3H).13C NMR (75
MHz, CD3OD) 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. 1H NMR (300 MHz, CD3OD) 4.46 (q, J=
7.3 Hz, 1H), 1.48 (d,J= 7.4 Hz, 3H).13C NMR (75 MHz, CD3OD) 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. 1H NMR (300 MHz, CD3OD) 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).13C NMR (75 MHz, CD3OD) 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] 1H NMR (300 MHz, CD3OD)
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. 1H NMR (300 MHz, CD3OD) 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). 13C NMR
(75 MHz, CD3OD) 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.
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
7/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
8/115
(489 mg, 2.4 mmol, 80%). The spectroscopic data were identical to those reported in the literature.[8] 1H
NMR (300 MHz, [D6] Acetone) 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 ofN-Boc protected chiral amino acid (1 equiv., 0.1 M) in DCM
were added methyl ester hydrochloride (1 equiv.), HOBt-0.8H2O (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 MHCl solution, water and finally brine. The organic layer was dried
over MgSO4 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 MgSO4 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 SOCl2 (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.
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
9/115
data were identical to those reported in the literature.[9] 1H NMR (300 MHz, CD3OD) 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 2O (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] 1H NMR (300 MHz, CDCl3) 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 fromN-Boc protected methyl ester dipeptide PEP1
(338 mg, 1.3 mmol) and 2 MNaOH 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] 1H NMR (300 MHz, CDCl3) 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 SOCl2(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] 1H NMR (300 MHz, CD3OD) 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 2O (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.
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
10/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
11/115
was obtained as a colorless crystalline solid (792 mg, 2.3 mmol, 88%). mp 124-126C. 1H NMR (300
MHz, CD3OD) 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, CD3OD) 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.
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
12/115
O
O
NH O
O
10
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
13/115
O
O
HN O
O
11a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
14/115
O
O
HN
O
O CCl3
11b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
15/115
O
O
HN
O
11c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
16/115
O
O
HN CF
3
O11d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
17/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
18/115
O
O
NH
O
12c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
19/115
O
O
N
H
CF3
O
12d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
20/115
O
O
HN O
O
13a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
21/115
O
O
HN O
O
Cl
ClCl
13b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
22/115
O
O
HN
O
13c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
23/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
24/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
25/115
O
O
HN
O
14c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
26/115
O
O
HN
F
O
FF
14d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
27/115
O
O
HN O
Cl
ClCl
O
15b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
28/115
O
O
HN
O
15c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
29/115
O
O
HN
F
O
FF
15d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
30/115
O
O
NH
O
O
16a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
31/115
O
O
N
H
O
O
Cl
Cl
Cl
16b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
32/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
33/115
O
O
NH
O
F
F
F
16d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
34/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
35/115
O
O
HN O
O
HN
O
O
17aa
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
36/115
O
O
HN O
O
Cl
ClCl
17b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
37/115
O
O
HN O
O
Cl
Cl
Cl
HN
O
OCl
Cl
Cl
17bb
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
38/115
O
O
HN
O
17c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
39/115
O
O
17cc
NH
O
HN
O
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
40/115
O
O
HN CF3
O
17d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
41/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
42/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
43/115
O
O
NH
O
O
Cl
Cl
Cl
NH
OO
Cl
ClCl
18bb
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
44/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
45/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
46/115
O
O
NH
CF3
ONH
CF3O
18dd
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
47/115
O
O
HN O
O
19a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
48/115
O
O
HN O
O
HN
O
O
19aa
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
49/115
O
O
HN O
O
Cl
ClCl
19b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
50/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
51/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
52/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
53/115
O
O
HN
O
F
FF
19d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
54/115
O
O
HN
O
F
F
F
HN
O
F
FF
19dd
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
55/115
O
O
HN O
O
20a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
56/115
O
O
HN O
Cl
O
ClCl
20b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
57/115
O
O
HN
O
20c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
58/115
O
O
HN
F
O
FF
20d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
59/115
O
O
HN
F
O
F
F
HN
O
F
F
F
20dd
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
60/115
O
O
HN O
O
21a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
61/115
O
O
HN O
Cl
O
ClCl
21b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
62/115
O
O
H
N
O
21c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
63/115
O
O
HN
F
O
FF
21d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
64/115
O
O
HN
F
O
FF
N
H
O
F
F
F
21dd
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
65/115
O
O
NH O
O
22a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
66/115
O
O
NH
O
ONH
O O
22aa
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
67/115
O
O
NH O
O
Cl
Cl
Cl
22b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
68/115
O
O
N
H
O
22c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
69/115
O
O
N
H
O
F
F
F
22d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
70/115
O
O
NH
O
F
F
F
NH
O
F
F
F
22dd
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
71/115
O
O
HN
O
F
F
F
NH
O
O
23a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
72/115
O
O
HN
O
NH
O
O
OCl
ClCl
23b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
73/115
O
O
HN
O
HN O
O
F
FF
24a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
74/115
O
O
HN
O
HN O
O
O
Cl
ClCl
24b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
75/115
O
O
HN
NH
O
O
O
25
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
76/115
O
O
NH
HN O
O
O26
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
77/115
O
N
27
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
78/115
O
N
28
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
79/115
O
O
HN
NH
O
O
O
29
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
80/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
81/115
O
O
NH
OHN O
O
31
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
82/115
O
O
N
H
OHN O
O
32
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
83/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
84/115
O
O
HN
O
HN
O
O
NH
O
O
34
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
85/115
O
O
NH
NH
O
O
O HN O
O
35
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
86/115
O
O
NH
O
O
HN
NH
O
O
O36
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
87/115
HO
H
N
O
O
AA1a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
88/115
HO
OHN
O
F
FF
AA2a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
89/115
HO
OHN O
O
Cl
ClCl
AA3a
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
90/115
HO NH
O O
AA1b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
91/115
HO
O
NH
O
F
F
F
AA2b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
92/115
HO
O
NH
O
Cl
ClCl
O
AA3b
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
93/115
HO
OHN
O
AA1c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
94/115
HO
O
NH
O
F
F
F
AA2c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
95/115
HO
OHN O
Cl
ClCl
O
AA3c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
96/115
HO
HN O
O
O
AA4c
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
97/115
HO
OHN
O
AA1d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
98/115
HO
OHN
O
F
FF
AA2d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
99/115
HO
OHN O
O
Cl
ClCl
AA3d
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
100/115
HO
OHN
O
AA1e
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
101/115
HO
OHN
O
F
FF
AA2e
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
102/115
HO
OHN O
O
Cl
ClCl
AA3e
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
103/115
HO
O
NH
O
AA1f
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
104/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
105/115
HO
O
NH
OCl
Cl
ClO
AA3f
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
106/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
107/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
108/115
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
109/115
HO
HN
O
NH
O
OO
PEPOH1
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
110/115
O NH2
O
HCl
AAMe2
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
111/115
NH
OHN O
O
O
O
PEP2
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
112/115
HOHN
ONH O
O
O
PEPOH2
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
113/115
O
O
HClNH2
AAMe3
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
114/115
O
OHN
O
N
H
O
O
PEP3
8/11/2019 Acylation of a-Amino Acids MeOH.pdf
115/115
HOHN
ONH O
O
O
PEPOH3