acylation of a-amino acids meoh.pdf

8/11/2019 Acylation of a-Amino Acids MeOH.pdf

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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*


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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


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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


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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.


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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.


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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.


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(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


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


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.


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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.


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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.


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O

O

NH O

O

10


13/115

O

O

HN O

O

11a


14/115

O

O

HN

O

O CCl3

11b


15/115

O

O

HN

O

11c


16/115

O

O

HN CF

3

O11d


17/115


18/115

O

O

NH

O

12c


19/115

O

O

N

H

CF3

O

12d


20/115

O

O

HN O

O

13a


21/115

O

O

HN O

O

Cl

ClCl

13b


22/115

O

O

HN

O

13c


23/115


24/115


25/115

O

O

HN

O

14c


26/115

O

O

HN

F

O

FF

14d


27/115

O

O

HN O

Cl

ClCl

O

15b


28/115

O

O

HN

O

15c


29/115

O

O

HN

F

O

FF

15d


30/115

O

O

NH

O

O

16a


31/115

O

O

N

H

O

O

Cl

Cl

Cl

16b


32/115


33/115

O

O

NH

O

F

F

F

16d


34/115


35/115

O

O

HN O

O

HN

O

O

17aa


36/115

O

O

HN O

O

Cl

ClCl

17b


37/115

O

O

HN O

O

Cl

Cl

Cl

HN

O

OCl

Cl

Cl

17bb


38/115

O

O

HN

O

17c


39/115

O

O

17cc

NH

O

HN

O


40/115

O

O

HN CF3

O

17d


41/115


42/115


43/115

O

O

NH

O

O

Cl

Cl

Cl

NH

OO

Cl

ClCl

18bb


44/115


45/115


46/115

O

O

NH

CF3

ONH

CF3O

18dd


47/115

O

O

HN O

O

19a


48/115

O

O

HN O

O

HN

O

O

19aa


49/115

O

O

HN O

O

Cl

ClCl

19b


50/115


51/115


52/115


53/115

O

O

HN

O

F

FF

19d


54/115

O

O

HN

O

F

F

F

HN

O

F

FF

19dd


55/115

O

O

HN O

O

20a


56/115

O

O

HN O

Cl

O

ClCl

20b


57/115

O

O

HN

O

20c


58/115

O

O

HN

F

O

FF

20d


59/115

O

O

HN

F

O

F

F

HN

O

F

F

F

20dd


60/115

O

O

HN O

O

21a


61/115

O

O

HN O

Cl

O

ClCl

21b


62/115

O

O

H

N

O

21c


63/115

O

O

HN

F

O

FF

21d


64/115

O

O

HN

F

O

FF

N

H

O

F

F

F

21dd


65/115

O

O

NH O

O

22a


66/115

O

O

NH

O

ONH

O O

22aa


67/115

O

O

NH O

O

Cl

Cl

Cl

22b


68/115

O

O

N

H

O

22c


69/115

O

O

N

H

O

F

F

F

22d


70/115

O

O

NH

O

F

F

F

NH

O

F

F

F

22dd


71/115

O

O

HN

O

F

F

F

NH

O

O

23a


72/115

O

O

HN

O

NH

O

O

OCl

ClCl

23b


73/115

O

O

HN

O

HN O

O

F

FF

24a


74/115

O

O

HN

O

HN O

O

O

Cl

ClCl

24b


75/115

O

O

HN

NH

O

O

O

25


76/115

O

O

NH

HN O

O

O26


77/115

O

N

27


78/115

O

N

28


79/115

O

O

HN

NH

O

O

O

29


80/115


81/115

O

O

NH

OHN O

O

31


82/115

O

O

N

H

OHN O

O

32


83/115


84/115

O

O

HN

O

HN

O

O

NH

O

O

34


85/115

O

O

NH

NH

O

O

O HN O

O

35


86/115

O

O

NH

O

O

HN

NH

O

O

O36


87/115

HO

H

N

O

O

AA1a


88/115

HO

OHN

O

F

FF

AA2a


89/115

HO

OHN O

O

Cl

ClCl

AA3a


90/115

HO NH

O O

AA1b


91/115

HO

O

NH

O

F

F

F

AA2b


92/115

HO

O

NH

O

Cl

ClCl

O

AA3b


93/115

HO

OHN

O

AA1c


94/115

HO

O

NH

O

F

F

F

AA2c


95/115

HO

OHN O

Cl

ClCl

O

AA3c


96/115

HO

HN O

O

O

AA4c


97/115

HO

OHN

O

AA1d


98/115

HO

OHN

O

F

FF

AA2d


99/115

HO

OHN O

O

Cl

ClCl

AA3d


100/115

HO

OHN

O

AA1e


101/115

HO

OHN

O

F

FF

AA2e


102/115

HO

OHN O

O

Cl

ClCl

AA3e


103/115

HO

O

NH

O

AA1f


104/115


105/115

HO

O

NH

OCl

Cl

ClO

AA3f


106/115


107/115


108/115


109/115

HO

HN

O

NH

O

OO

PEPOH1


110/115

O NH2

O

HCl

AAMe2


111/115

NH

OHN O

O

O

O

PEP2


112/115

HOHN

ONH O

O

O

PEPOH2


113/115

O

O

HClNH2

AAMe3


114/115

O

OHN

O

N

H

O

O

PEP3


115/115

HOHN

ONH O

O

O

PEPOH3

acylation of a-amino acids meoh.pdf

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