Electronic Supplementary InformationElectronic Supplementary Information . Ester vs. amide on...

S1

Electronic Supplementary Information

Ester vs. amide on folding: A case study with a 2-residue synthetic peptide

Kuruppanthara N. Vijayadas, † Roshna V. Nair, † Rupesh L. Gawade, ‡ Amol S. Kotmale, §Panchami Prabhakaran, †,¥ Rajesh G. Gonnade, ‡

Vedavati G. Puranik, ‡Pattuparambil. R. Rajamohanan, §and Gangadhar J. Sanjayan *,†

†Division of Organic Chemistry, §Central NMR Facility, ‡Center for Materials Characterization, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411

008, India. ¥Department of Chemistry & Biology, University of Leeds, LS2 9JT, UK.

Contents S1

General methods S2

Synthetic Scheme S3

Experimental procedures S4-S12

Mass spectra of compounds S13-S19

1H NMR spectra of compounds S20-S26

13C and DEPT-135 spectra of compounds S27-S39

2D COSY and TOCSY spectra of compounds 1 and 5 (amides) S40-S43

2D COSY and TOCSY spectra of compounds 6 and 10 (esters) S44-S48

2D NOESY spectra of compounds 1 and 5 (amides) S49-S50

2D NOESY spectra of compound 6 and 10 (esters) S51-S52

NMR titration studies of compounds 1, 5, 10 S53-S55

Crystal Data Table-Hydrogen bonding parameters and Crystal Data S56- S61

References S61

Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2013

S2

General Methods.

Unless otherwise stated, all the chemicals and reagents were obtained commercially. Dry

solvents were prepared by the standard procedures. Analytical Thin Layer

Chromatography was done on pre-coated silica gel plates (Kieselgel 60F254, Merck).

Column Chromatographic purifications were done with 100-200 or 230-400 Mesh Silica

gel. NMR spectra were recorded in CDCl3 or DMSO-d6 on AV 200 MHz, AV 400 MHz

or AV 500 MHz spectrometers. All chemical shifts are reported in δ ppm downfield to

TMS and peak multiplicities as singlet (s), doublet (d), quartet (q), broad singlet (bs), and

multiplet (m). The DMSO-d6 titration studies were done in CDCl3. Elemental analyses

were performed on an Elmentar-Vario-EL (Heraeus Company Ltd., Germany). IR spectra

were recorded in CHCl3 using Shimadzu FTIR-8400 spectrophotometer. Melting points

were determined on a Buchi Melting Point B-540. Electron Scattered Ionization (ESI)

Mass Spectrometric measurements were done with API QSTAR Pulsar mass

Spectrometer. Single crystal X-ray data were collected on a Bruker SMART APEX CCD

Area diffractometer with graphite monochromatized (Mo Ka = 0.71073Å) radiation at

room temperature or less.


S3

Synthetic Scheme

NH

O

OH

N

ON

H

R1

R2

O

H

NH

O

RH

12 R1 = tBoc L-Pro, R2 = OBn, (86%) 2 R1 = tBoc L-Pro, R2 = NHMe, (95%)13a R1 = tBoc, R2 = 4-Br anilide, (87%)13b R1 = H, R2 = 4-Br anilide 1 R1 =Acetyl, R2 = 4-Br anilide, (88%) 3 R1 = Ethyloxycarbonyl, R2 = 4-Br anilide, (64%) 4 R1 = Trifluoroacetyl, R2 = 4-Br anilide, (90%) 5 R1 = iButyloxycarbonyl, R2 = 4-Br anilide, (81%) 6 R1 = tBoc, R2 = OMe, (71%) 7 R1 = tBoc, R2 = OBn, (56%) 8 R1 = Ethyloxy carbonyl, R2 = OMe, (80%) 9 R1 = Ethyloxy carbonyl, R2 = borneol, (87%)10 R1 = iButyloxy carbonyl, R2 = OMe, (63%)11 R1 = Benzoyl, R2 = OMe, (68%)

a R = tBocb R = tBoc L-Proc R = iButyloxy carbonyld R = Ethyloxy carbonyle R = H

a R = 4-Br-C6H4-NHb R = OBnc R = OMe

a

R

cd

efgh

14 15

14a + 15b

14a + 15b14d + 15c

i

14e + 15c14c + 15c

1-13

aj

il

k

14a + 15a

14a + 15c

b

Reagents and Conditions

(a) DCC, HOBt, DCM, rt, 12h; (b) methanolic MeNH2, rt, 3h; (c) EDC.HCl, HOBt,

DCM, rt, 12h; (d) TFA, DCM, rt, 3h; (e) AcCl, Et3N, DCM, rt, 12h; (f) Ethyl

chloroformate, Et3N, DCM, rt, 12h; (g) Trifluoroacetic anhydride, Et3N, DCM, rt, 12h;

EDC.HCl, HOBt, DCM, rt-12h; (h) Isobutyl chloroformate, Et3N, DCM, rt, 12h; (i)

EDC.HCl, DMAP, DCM, rt, 12h; (j) HBTU, DIPEA, MeCN, rt, 12h; (k) (i) LiOH.H2O,

MeOH, H2O, rt, 12h, (ii) DCC, DMAP, Borneol, rt, 12h; (l) (i) Na2CO3, BzCl, THF, rt,

12h, (ii) DBU, DMF, 4A mol. sieves, rt, 3h.


S4

Experimental Procedures

2-(Tert-butoxycarbonylamino)benzoic acid, 14a:1

To a solution of anthranilic acid (1g, 6.6mmoles) in dioxane (15mL)

and water (7.5mL), NaOH (0.528, 13.2 mmoles) was added

followed by the addition of tBoc-anhydride (1.7g, 7.9mmoles). The

reaction mixture was stirred at room temperature for 3 hours. The

solvents were evaporated under reduced pressure. The residue was acidified with

saturated potassium bisulphate solution, followed by extraction with DCM (10mL X 3).

Evaporation under reduced pressure afforded the crude product 14a, which was used for

further reactions, without purification.

2-((Isobutoxycarbonyl)amino)benzoic acid, 14c:2

To a solution of anthranilic acid (1g, 6.6mmoles) in dioxane

(15mL) and water (7.5mL), NaOH (0.528, 13.2 mmoles) was

added followed by the addition of isobutyl chloroformate (1.7g,

7.9mmoles). The reaction mixture was stirred at room

temperature for 3 hours, after which the solvents were evaporated

under reduced pressure. The residue was acidified with saturated potassium bisulphate

solution, followed by extraction with DCM (10mL X 3). Evaporation under reduced

pressure afforded the crude product 14c, which was used for further reactions, without

purification.

Methyl 2-((ethoxycarbonyl)amino)benzoate, 16:

To a solution of anthranilic methyl ester (0.5g, 3.3mmoles) in

dry DCM (10mL) containing DIPEA (1.25g, 1.7mL, 9.92

mmoles) was added ethyl chloroformate (0.43g, 3.92 mmoles),

drop wise with vigorous stirring. The reaction mixture was

stirred at room temperature for 12 h. The reaction mixture was diluted with DCM and the

organic layer was washed sequentially with saturated sodium bicarbonate, potassium

bisulphate and water. The organic layer was dried over anhydrous Na2SO4 solution and

evaporated under reduced pressure to furnish the crude product which was purified by

column chromatography, (85:15 pet. ether/ethyl acetate, Rf: 0.5) affording 16 as a white

solid (0.63g, 93%), mp: 60-61oC; IR (CHCl3, ν (cm-1): 3310, 3021, 2401, 1731, 1694,

COOH

NH

OO

COOH

NH

OO

COOCH3

NH

OO


S5

1591, 1529, 1453, 1315, 1245, 1216; 1H NMR (CDCl3/200MHz): δ ppm 10.47 (s, 1H),

8.42-8.46 (d, J=8.23Hz, 1H), 7.97-8.01 (dd, J=7.98Hz, J=1.63Hz 1H), 7.47-7.56 (m, 1H),

6.96-7.05 (m, 1H), 4.17-4.27 (q, 2H), 3.90 (s, 3H), 1.28-1.35 (t, 1H, J=7.07), 13C NMR

(CDCl3,125MHz): δ ppm 168.4, 153.6, 141.8, 134.5, 130.8, 121.3, 118.7, 114.3, 61.1,

52.1, 14.4; LC-MS: 247.06 (M+23)+; Elemental Analysis calculated for C11H13NO4: C,

59.19; H, 5.87; N, 6.27; Found: 58.65; H, 5.16; N, 5.94.

Representative procedure for ester hydrolysis:

2-((Ethoxycarbonyl)amino)benzoic acid, 14d

To a solution of 16 (0.5g) in methanol (5mL), LiOH (0.18, 0.008mmol) in water (5mL)

was added. After stirring for 12h, the reaction mixture was stripped of the solvent under

reduced pressure, acidified using saturated KHSO4 solution and then extracted with ethyl

acetate (3x5mL). The organic layer was evaporated under reduced pressure to obtain the

free acid 14d which was used for next reaction, without further purification.

Representative procedure for peptide coupling (for specific coupling agents, see

scheme-1):

(S)-tert-butyl 2-(2-(4-bromophenylcarbamoyl)pyrrolidine-1-

carbonyl)phenylcarbamate, 13a:

To a solution of 15a (0.25g, 0.9949mmole) in dry DCM

(5mL), Boc-Ant-OH (0.5g, 1.8903mmoles), EDC.HCl

(0.286g, 1.4924) and HOBt (0.062g, 25wt %) were

added. After stirring at room temperature for 12 hours,

the reaction mixture was diluted with DCM and washed

sequentially with saturated sodium bicarbonate,

potassium bisulphate solution and water. The washings were extracted with DCM

(10mLx2) and dried with anhydrous Na2SO4 and evaporated under reduced pressure. The

crude residue thus obtained was purified by column chromatography, (50:50 pet

ether/ethyl acetate, Rf: 0.5) furnishing 13a as a white solid (0.4181g, 87%), mp: 97-

101oC; [α]28D: -28.89° (c = 1.066, CHCl3); IR (CHCl3, ν (cm-1): 3279, 3018, 2359, 1730,

1681, 1614, 1537, 1429, 1367, 1300, 1247, 1159, 1074; 1H NMR (CDCl3/500MHz): δ

ppm 9.59 (s, 1H), 8.46(s, 1H), 8.26-8.28 (d, J=8.26Hz, 1H), 7.43 (t, J=7.43Hz, 1H), 7.36-

7.37 (d, J=7.43Hz, 1H), 7.25-7.26 (d, J=8.8Hz,2H), 7.15-7.16 (d, 2H, J=8.8Hz), 7.07 (t,

NHO

O

N HN

O

Br

H

O


S6

1H, J=7.43Hz), 5.01-5.04 (m, 1H), 3.60-3.65 (m, 1H), 3.49-3.53(m, 1H), 2.23-2.37 (m,

2H) 2.03-2.11 (m, 1H) 1.85-1.93 (m, 1H) 1.55(s, 9H); 13C NMR (CDCl3,125MHz): δ

ppm 169.7, 153.1, 137.2, 136.7, 131.3, 131.1, 126.8, 123.9, 122.0, 120.8, 120.1, 116.1,

80.6, 60.7, 50.5, 28.9, 25.1; ESI-MS: 490.3465 (M+2H)+; 510.3085 (M+Na)+; 428.2927

(M+K)+; Elemental Analysis calculated for C23H26BrN3O4: C, 56.56; H, 5.37; N, 8.60;

Found: C, 56.18; H, 5.87; N, 8.10.

Representative procedure for tBoc deprotection using TFA/DCM.

(S)-1-(2-aminobenzoyl)-N-(4-bromophenyl)pyrrolidine-2-carboxamide, 13b:

To a solution of 13a (0.1, 0.2577mmol) in DCM (1mL)

maintained at 0oC, trifluoroaceticacid (1 mL) was added

drop wise. The reaction mixture was stirred at 0oC for 10

minutes and then at RT for 3 h. The residue obtained

after evaporating the volatiles was neutralized using

saturated solution of sodium bicarbonate and extracted repeatedly using DCM (3x5mL).

The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced

pressure to obtain the amine 13b which was used for next reaction, without further

purification.

(S)-1-(2-acetamidobenzoyl)-N-(4-bromophenyl)pyrrolidine-2-carboxamide, 1:

To a solution of 13b (0.1 gm, 0.2583mmol) in DCM (5

mL), Et3N (0.11mL, 0.77507mmol) and acetyl chloride

(0.03mL, 0.3875mmol) were added. After stirring for 12

hours, the reaction mixture was diluted with DCM (5

mL) and the organic layer was washed with saturated

sodium bicarbonate (5mL), potassium bisulphate (5mL) and water (5mL). The organic

layer was dried over anhydrous Na2SO4 solution and evaporated under reduced pressure

to get the crude product which was purified by column chromatography, (20:80 pet.

ether/ethyl acetate, Rf: 0.5) affording 1 as a white solid (0.98g, 88%), crystallized from a

solution of methanol and dichloromethane, mp: 226-229oC; [α]24D: -90° (c = 0.4, CHCl3);

IR (CHCl3) ν (cm-1) 3261, 3020, 2401, 2360, 2343, 1716, 1697, 1683, 1653, 1647,

1635, 1620; 1H NMR(CDCl3/200MHz): δ ppm 9.47 (s, 1H), 9.29 (s, 1H), 8.35-8.39 (d,

NHO

O

N HN

O

Br

H

NH2O

N HN

O

Br

H


S7

1H, J=8.06Hz), 7.38-7.47 (dd, 1H, J=15.62 Hz, J=1.59 Hz), 7.11-7.32 (m, 6H), 4.95-5.01

(m, 1H), 3.39-3.63 (m, 2H), 2.24 (s, 3H), 1.87-2.46 (m, 4H), 13C NMR (DMSO-

d6,100MHz): δ ppm 171.3, 168.9, 167.5, 138.4, 135.0, 131.9, 129.9, 128.5, 126.8, 123.9,

121.9, 121.5, 115.4, 60.4, 49.3, 30.2, 24.9, 24.1; LC-MS: 454.05 (M+Na)+; Elemental

Analysis calculated for C20H20BrN3O3: C, 55.83; H, 4.68; N, 9.77; Found: C, 57.36; H,

5.14; N, 8.96.

(S)-1-(2-Trifluroacetamidobenzoyl)-N-(4-bromophenyl)pyrrolidine-2-carboxamide,

4:

Compound 4, obtained by following the procedure used

for preparation of 1 (vide supra), except using trifluoro

acetic anhydride as the acylating agent, was purified by

column chromatography (20:80 pet. ether/ethyl acetate,

Rf: 0.5), white solid (0.112g, 90%), crystallized from

methanol, mp: 210-217oC; [α]27D: -199° (c = 0.1,

CHCl3); IR (CHCl3) ν (cm-1) 3310, 3020, 2400, 1733, 1698, 1621, 1531, 1422, 1215; 1H

NMR(CDCl3/200MHz): δ ppm 10.63 (s, 1H), 9.04 (s, 1H), 8.33-8.38 (d, 1H, J=8.03Hz),

7.52-7.60 (m, 2H), 7.26-7.42 (m, 6H), 4.90-4.97 (m, 1H), 3.61-3.80 (m, 2H), 1.87-2.55

(m, 4H), 13C NMR (50 MHz, CDCl3) δ : ppm 169.6, 168.7, 136.8, 134.5, 131.9, 131.7,

128.1, 125.0, 124.4, 122.3, 121.2, 116.8, 61.0, 51.2, 27.8, 25.4; ESI-MS: 508.6183

(M+Na)+; 524.6121 (M+K)+. Elemental Analysis calculated for C20H17BrF3N3O3: C,

49.60; H, 3.54; N, 8.68; Found: C, 47.37; H, 6.46; N, 8.16.

(S)-ethyl 2-(2-(4-bromophenylcarbamoyl)pyrrolidine-1-carbonyl)phenylcarbamate,

3:

Compound 3, obtained by following the procedure used

for preparation of 1 (vide supra), except using ethyl

chloroformate as the acylating agent, was purified by


Rf: 0.5), white solid (0.076g, 64%), crystallized from a

solution of methanol and dichloromethane, mp: 201-

203oC; [α]26D: -141° (c = 0.1, CHCl3); IR (CHCl3, ν (cm-1): 3421, 3020, 2400, 1733,

1687, 1616, 1541, 1427, 1398, 1302, 1215; 1H NMR (CDCl3/400MHz): δ ppm 9.58 (s,

NHO

O

N HN

O

Br

H

FF

F

NHO

O

O

N HN

O

Br

H


S8

1H), 8.66(s, 1H), 8.25-8.27 (d, J=8.18Hz, 1H), 7.43-1.47 (t, J=7.77Hz, 1H), 7.38-7.39 (d,

J=7.40Hz, 1H), 7.25-7.27 (d, J=8.7Hz,2H), 7.15-7.18 (d, 2H, J=8.51Hz), 7.08-7.12 (t,

1H, J=7.40Hz), 5.00-5.03 (m, 1H), 4.22-4.27 (m, 2H), 3.60-3.70 (m, 1H), 3.50-3.56 (m,

1H), 2.23-2.39 (m, 2H), 2.04-2.14 (m, 1H) 1.84-1.94 (m, 1H), 1.32-1.35 (t, 3H, J=7.15); 13C NMR (CDCl3,125MHz): δ ppm 169.8, 153.9, 137.2, 136.5, 131.3, 131.2, 126.8,

123.9, 122.3, 120.8, 120.3, 116.2, 61.3, 60.9, 50.7, 28.9, 25.1, 14.4; LC-MS: 482.08

(M+Na)+; Elemental Analysis calculated for C21H22BrN3O4: C, 54.79; H, 4.82; 9.13;

Found: C, 58.16; H, 4.38; N, 8.92.

(S)-Isobutyl 2-(2-(4-bromophenylcarbamoyl)pyrrolidine-1-carbonyl)phenyl

Carbamate, 5: Compound 5, obtained by following the procedure used

for preparation of 1 (vide supra), except using isobutyl

chloroformate as the acylating agent, was purified by


Rf: 0.55), white solid (0.102g, 81%), mp: 200-203oC;

[α]27D: -142° (c = 0.1, CHCl3); IR (CHCl3, ν (cm-1):

3316, 3020, 2400, 1734, 1686, 1617, 1541, 1457, 1398, 1302, 1215; 1H NMR

(CDCl3/200MHz): δ ppm 9.45 (s, 1H), 8.61 (s, 1H), 8.19-8.23 (d, J=8.27Hz, 1H), 6.99-

7.41 (m, 7H), 4.91-4.97 (m, 1H), 3.89-3.92 (d, 1H, J=6.54), 3.36-3.61 (m, 2H), 1.75-2.25

(m, 5H), 0.91-0.94 (d, 6H, J=6.54; 13C NMR (CDCl3,125MHz): δ ppm 169.7, 153.1,

137.2, 136.7, 131.3, 131.1, 126.8, 123.9, 122.0, 120.8, 120.1, 116.1, 80.6, 60.7, 50.5,

28.9, 25.1; ESI-MS: 488.4006 (M+H)+; 510.2612; (M+Na)+; Elemental Analysis

calculated for C23H26BrN3O4: C, 56.56; H, 5.37; Br, 16.36; N, 8.60; Found: C, 56.19; H,

5.85; N, 8.98.

(S)-Tert-butyl 2-(2-((S)-2-(benzyloxycarbonyl)pyrrolidine-1-carbonyl)phenyl

carbamoyl)pyrrolidine-1-carboxylate, 12

Compound 12, obtained by following the coupling

procedure used for the preparation of 13a (vide

supra), was purified by column chromatography (50%

ethyl acetate/pet. ether, Rf: 0.4), waxy liquid (1.34 g,

86%); [α]26D: -74.6° (c 0.34, CHCl3); IR (ν) neat (cm-

NHO

O

O

N HN

O

Br

H

NHO

O

NO

O

H

NH

O

O


S9

1) 3307, 3066, 2978, 1743, 1692, 1627, 1596, 1525, 1404, 1215, 1165, 1121, 1088, 1031; 1H NMR (400 MHz, CDCl3) δ: 9.76rotamer (0.55H), 9.67rotamer (0.45H), 8.50-8.35 (m, 1H),

7.5-7.0 (m, 8H), 5.28-5.19 (m,1H), 4.78-4.75 (m, 1H), 4.43rotamer (0.55H), 4.26 rotamer

(0.45H), 3.80-3.42 (m, 4H), 2.38-1.8 (m, 8H), 1.48rotamer (4.3H), 1.40rotamer (4.7H); 13C

NMR (100 MHz, CDCl3) δ: 171.6, 171.3, 168.1, 154.7, 153.7, 136.6, 135.97, 135.3,

130.9, 130.5, 128.2, 127.98, 127.7, 127.1, 126.9, 124.4, 123.3, 122.9, 122.5, 122.8, 122.5,

121.3, 120.6, 79.5, 66.7, 66.6, 61.9, 61.1, 58.7, 49.8, 49.6, 46.8, 46.4, 31.0, 29.9, 28.8,

28.1, 27.9, 24.8, 24.0, 23.5; ESI MS: 522.5042 (M+H)+, 544.5149 (M+Na)+, 560.5602

(M+K)+; Elemental analyses calculated for C29H35N3O6: C, 66.78; H, 6.76; N, 8.06;

Found: C, 67.01; H, 6.93; N, 7.69.

(S)-tert-butyl 2-(2-((S)-2-(methylcarbamoyl)pyrrolidine-1-carbonyl) phenyl

carbamoyl)pyrrolidine-1-carboxylate, 2:

The ester 12 (0.45 g, 0.86 mmol) was converted into its

corresponding methyl amide 2 by stirring the compound in

methanolic methyl amine at room temperature. After

completion of the reaction (3 h), the solvent was stripped off

and the product was taken in dichloromethane, washed with

water and the organic layer was dried over anhydrous sodium

sulfate. Evaporation under reduced pressure and purification by

column chromatography afforded 12 (5% methanol /ethyl acetate, Rf: 0.5), 0.36 g, 95%, ;

mp: 185-187 oC; [α]26D: -120° (c 0.2, CHCl3); IR (ν) nujol (cm-1): 3273, 2726, 1698,

1655, 1618, 1586, 1460, 1377, 1307, 1215, 1156; 1H NMR (400 MHz, CDCl3) δ:

10.01rotamer (0.5H), 9.71-9.56rotamer (0.5H), 8.44-8.13 (m, 1H), 7.41 (b, 2H), 7.13-7.09 (t, J

= 7.41 Hz, 1H), 6.70 (bs, 1H), 4.7-4.63 (b, 1H), 4.42rotamer (0.4H), 4.29rotamer (0.6H),

3.8-3.4 (m, 4H), 4.85-4.84 (d, J = 4.72 Hz, 3H), 2.4-1.8 (m, 8H), 1.48rotamer (s, 4H),

1.38rotamer (s, 5H); 13C NMR (100 MHz, CDCl3) δ: 172.2, 171.9, 171.8, 169.2, 168.9, 155,

154.2, 136.6, 136.0, 135.3, 131.1, 130.5, 130.3, 126.8, 123.9, 123.5, 123.3, 122.9, 122.5,

120.9, 80.1, 79.9, 62.0, 60.96, 60.1, 50.3, 49.7, 47.1, 46.7, 31.8, 31.3, 29.9, 28.9, 28.2,

26.2, 25.1, 24.3, 23.7, 22.8; ESI MS: 445.3834 (M+H)+, 467.3785 (M+Na)+, 483.36

(M+K)+; Elemental analyses calculated for C23H32N4O5: C, 62.14; H, 7.26; N, 12.60;

Found: C, 61.86; H, 7.14; N,12.98.

NHO

O

N HN

O

H

NH

O

O


S10

(S)-Benzyl 1-(2-(tert-butoxycarbonylamino)benzoyl)pyrrolidine-2-carboxylate, 7:

Preparation of this compound is reported.1 7 was

crystallized from a mixture of ethylacetate and pet.

ether.

(S)-Methyl 1-(2-(tert-butoxycarbonylamino)benzoyl)pyrrolidine-2-carboxylate, 6:

Compound 6, obtained by following the coupling procedure

used for the preparation of 13a (vide supra), was purified by

column chromatography (30:70 pet. ether/ethyl acetate, Rf:

0.5), 3.7 g, 71%, white solid, crystallized from a solution of

methanol and dichloromethane; mp: 94-96 °C; [α]27D: -91° (c =

0.1, CHCl3); IR (CHCl3) ν (cm-1) 3368, 3020, 2982, 1724,

1625, 1596, 1522, 1454, 1414, 1216, 1159, 1052, 1026; 1H NMR (200 MHz, CDCl3) δ:

8.33 (s,1H), 8.13-8.18 (d, J = 8.36 Hz, 1H), 7.32-7.39 (m, 2H), 6.95-7.03 (t, J = 7.22 Hz,

1H), 4.63-4.70 (m, 1H), 3.77 (s, 3H) 3.40-3.65 (m, 2H), 2.25-2.42 (m, 1H), 1.79-2.10 (m,

3H), 1.48 (s, 9H); 13C NMR (50 MHz, CDCl3) δ: 172.4, 168.7, 152.9, 137.2, 130.9,

128.6, 127.1, 123.3, 121.5, 120.0, 80.2, 59.0, 52.3, 49.9, 29.2, 28.2, 25.2; LC-MS: 371.02

(M+Na)+; Elemental analyses calculated for C18H24N2O5: C, 62.05; H, 6.94; N, 8.04;

Found: C, 61.99; H, 7.07; N, 8.58.

(S)-Methyl 1-(2-(iso-butoxycarbonylamino)benzoyl)pyrrolidine-2-carboxylate, 10:




0.5), 0.32g, 63%, white solid, crystallized from a solution of

diethyl ether and pet-ether; mp: 76-80 °C; [α]27D: -92° (c = 0.1,

CHCl3); IR (CHCl3) ν (cm-1) 3366, 3020, 2959, 1733, 1625,

1597, 1524, 1456, 1415, 1216, 1113, 1058; 1H NMR (400

MHz, CDCl3) δ: 8.54 (s,1H), 8.17-8.21 (d, J = 8.28 Hz, 1H), 7.31-7.43 (m, 2H), 7.00-

NHO

O

NO

O

H

O

NHO

O

O

N

O

HO

NHO

O

O

N

O

HO


S11

7.08 (m, 1H), 4.66-4.73 (m, 1H), 3.91-3.95 (m, 2H), 3.79 (s, 3H), 3.42-3.65 (m, 2H),

2.27-2.44 (m, 1H), 1.78-2.16 (m, 4H), 0.95-0.98 (d, J=6.61, 6H); 13C NMR (50 MHz,

CDCl3) δ: 172.6, 168.7, 153.9, 136.9, 131.1, 127.1, 123.7, 121.9, 120.1, 71.2, 59.0,

52.4, 49.9, 29.3, 27.9, 25.2, 18.9; LC-MS: 371.11 (M+Na)+; Elemental analyses

calculated for C18H24N2O5: C, 62.05; H, 6.94; N, 8.04; Found: C, 62.37; H, 6.67; N, 8.35.

(S)-Methyl 1-(2-(Ethyloxycarbonylamino)benzoyl)pyrrolidine-2-carboxylate, 8:




0.5), 0.32g, 80%, white solid, crystallized from a solution of

ethyl acetate and pet-ether; mp: 76-80 °C; [α]26D: -103° (c =

0.1, CHCl3); IR (CHCl3) ν (cm-1) 3378, 3020, 2400, 1732,

1626, 1597, 1525, 1416, 1215; 1H NMR (200 MHz, CDCl3) δ: 8.49 (s,1H), 8.14-8.19 (d,

J = 8.58 Hz, 1H), 7.33-7.41 (m, 2H), 6.98-7.05 (t, J = 7.20 Hz, 1H), 4.63-4.70 (m, 1H),

4.12-4.23 (m, 2H), 3.77 (s, 3H), 3.40-3.64 (m, 2H), 2.25-2.46 (m, 1H), 1.79-2.10 (m,

3H), 1.23-1.30 (t, J=7.18, 3H); 13C NMR (50 MHz, CDCl3) δ: 172.4, 168.6, 153.7, 136.8,

131.0, 127.1, 123.4, 121.9, 120.0, 61.01, 59.0, 52.3, 49.9, 29.3, 25.2, 14.3; LC-MS:

343.06 (M+Na)+; Elemental analyses calculated for C16H20N2O5: C, 59.99; H, 6.24; N,

8.74; Found: C, 59.37; H, 5.67; N, 9.12.

(2S)-((2R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl) 1-(2-(ethoxycarbonylamino)

benzoyl)pyrrolidine-2-carboxylate, 9:

Compound 8 (0.2 g, 0.625 mmol) was first subjected to

ester hydrolysis following the general procedure (vide

supra). The free acid thus obtained was subjected to

peptide coupling as mentioned in the representative

procedure for 13a (70:30 pet. ether/ethyl acetate, Rf:

0.5) to afford 9 (0.242g, 87%) as a white solid,

crystallized from a solution of ethyl acetate and pet-ether; mp: 127-128 °C; [α]27D: -93°

(c = 0.1, CHCl3); IR (CHCl3) ν (cm-1) 3448, 3020, 1726, 1626, 1597, 1524, 1455, 1418,

1216; 1H NMR (200 MHz, CDCl3) δ: 8.70 (s,1H), 8.13-8.29 (m, 1H), 7.36-7.43 (m, 2H),

6.93-7.06 (m, 1H), 4.99-5.06 (m, 1H), 4.67-4.83 (m, 1H), 4.13-4.23 (m, 2H), 3.48-3.86

NHO

O

O

N

O

HO

NHO

O

O

N

O

HO


S12

(m, 2H), 2.28-2.47 (m, 2H), 1.85-2.11 (m, 4H), 1.63-1.82 (m, 3H), 1.12-1.40 (m, 5H),

0.84-0.91 (m, 9H); 13C NMR (50 MHz, CDCl3) δ: 172.2, 168.5, 153.8, 137.3, 131.1,

127.2, 123.2, 121.7, 120.0, 80.7, 61.0, 59.5, 50.0, 49.0, 47.9, 44.8, 36.4, 29.3, 27.9, 27.1,

25.3, 19.6, 18.7, 14.4, 13.5; LC-MS: 465.23 (M+Na)+, 481.21 (M+K)+; Elemental

analyses calculated for C25H34N2O5: 67.85; H, 7.74; N, 6.33; Found: 67.69; H, 7.52; N,

6.52.

(S)-Methyl 1-(2-benzamidobenzoyl)pyrrolidine-2-carboxylate, 11: To an ice cold solution of 2-phenyl benzoxazinone3 (1 g, 4.48

mmol) and proline methyl ester (1 g, 5.83 mmol) in dry DMF

(20 ml) containing 4Å molecular sieves, DBU (2.05g, 2ml,

13.44mmol) was added drop wise. The reaction mixture was

allowed to stir at 0 °C for 10 minutes and then for 3 h at room

temperature. The reaction mixture was diluted with DCM, and

the organic layer was washed with water and dried using

an.Na2SO4. The crude product obtained after the removal of solvent under reduced

pressure was purified by column chromatography (50:50 pet. ether/ethyl acetate, Rf: 0.5)

to afford 11 (1.08 g, 68%), white solid, crystallized from a solution of diethyl ether and

pet-ether; mp: 116-120 °C; [α]25D: -50° (c = 0.1, CHCl3); IR (CHCl3) ν (cm-1) 3337,

3015, 2445, 1743, 1668, 1594, 1520, 1416, 1216; 1H NMR (400 MHz, CDCl3) δ: 10.32

(s,1H), 8.53-8.57 (d, J = 8.49 Hz, 1H), 7.90-7.95 (m, 2H), 7.34-7.53 (m, 5H), 7.06-7.13

(m, 1H), 4.61-4.67 (m, 1H), 3.51-3.73 (m, 2H), 3.66 (s, 3H), 2.20-2.38 (m, 1H), 1.73-

2.06 (m, 3H); 13C NMR (50 MHz, CDCl3) δ : 172.2, 168.9, 165.2, 162.4, 137.2, 134.3,

131.7, 131.2, 128.4, 127.4, 127.2, 123.6, 122.6, 121.7, 59.1, 52.1, 50.3, 36.3, 31.2, 29.0,

25.0; LC-MS: 375.05 (M+Na)+; Elemental analyses calculated for C20H20N2O4: C, 68.17;

H, 5.72; N, 7.95; Found: C, C, 68.43; H, 5.43; N, 7.68.

NHO

O

N

O

HO


S13

(M+H)+

(M+Na)+

(M+K)+

NHO

O

O

N HN

O

Br

H

13a

ESI-MS

(M+Na)+

NHO

O

N HN

O

Br

H

1 LC-MS


S14

(M+Na)+

NHO

O

O

N HN

O

Br

H

3

LC-MS

(M+H)+

(M+Na)+

NHO

O

O

N HN

O

Br

H

5

ESI-MS


S15

(M+Na)+

(M+H)+

(M+K)+ ESI-MS

NN

OO

NN

OO

HH

NNOO

OO

OO

OO12

(M+Na)+

(M+K)+ ESI-MS

NN

OO

NN

OO

HH

NNOO

NN

OO

HH

OO

(M+H)+

2


S16

(M+Na)+

NHO

O

O

N

O

HO

6

LC-MS

(M+Na)+

NHO

O

O

N

O

HO

10

LC-MS


S17

(M+Na)+

COOCH3

NH

OO

16

LC-MS

(M+Na)+

NHO

O

O

N

O

HO

8

LC-MS


S18

(M+Na)+

(M+K)+

NHO

O

N HN

O

Br

H

FF

F 4

ESI-MS

(M+Na)+

NHO

O

N

O

HO

11

LC-MS


S19

(M+Na)+

(M+K)+

NHO

O

O

N

O

HO

LC-MS

9


S20

10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5

9.58

8.46

8.28

8.26

7.43

7.37

7.36

7.26

7.25

7.17

7.15

7.09

7.07

5.04

5.03

5.01

3.64

3.63

3.61

3.53

3.52

3.51

3.50

2.34

2.33

2.31

2.27

2.07

2.06

1.90

1.55

NHO

O

N HN

O

Br

H

O

13a

1H NMR (CDCl3/500MHz)

0.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0

9.47

9.29

8.35

7.43

7.32

7.28

7.28

7.27

7.22

7.18

7.18

7.14

5.01

4.99

4.97

4.95

3.60

3.58

3.55

3.51

3.48

3.45

3.42

2.36

2.32

2.26

2.24

2.21

2.07

NHO

O

N HN

O

Br

H

1



S21

10 9 8 7 6 5 4 3 2

9.58

8.66

8.27

8.25

7.45

7.39

7.38

7.27

7.25

7.18

7.15

7.12

7.10

5.03

5.02

5.00

4.27

4.26

4.24

4.22

3.65

3.62

3.55

3.53

3.52

2.35

2.33

2.32

2.30

2.28

2.11

2.09

2.07

1.35

1.33

NHO

O

O

N HN

O

Br

H

3


0 9 8 7 6 5 4 3 2 1

9.45

8.61

8.23

8.19

7.41

7.37

7.33

7.30

7.26

7.19

7.15

7.08

7.04

6.99

4.97

4.94

4.91

3.92

3.89

3.61

3.55

3.52

3.44

2.25

2.22

2.19

2.00

1.97

1.95

1.91

1.88

1.85

1.82

0.94

NHO

O

O

N HN

O

Br

H

5



S22

0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5

1.40

1.48

1.97

2.15

2.35

3.42

3.53

3.63

3.80

4.26

4.43

4.75

4.77

4.78

5.19

5.22

5.25

5.28

7.10

7.39

8.35

8.41

8.51

9.67

9.76

NHO

O

N

O

HO

N

O

OH

17

1H NMR (400 MHz, CDCl3)

0.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5

1.38

1.48

2.31

3.43

3.55

3.65

4.31

4.40

4.63

4.69

6.70

7.09

7.11

7.13

7.27

7.41

7.95

8.13

8.20

8.27

8.44

9.57

9.71

10.0

1

NHO

O

N

O

H HN

N

O

OH

2



S23

.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5

CDCl3

8.33

8.18

8.13

7.39

7.35

7.32

7.27

7.03

6.99

6.95

4.70

4.68

4.66

4.63

3.77

3.62

3.60

3.58

3.56

3.53

3.50

3.48

2.33

2.07

2.04

2.01

1.99

1.98

1.95

1.92

1.48

NHO

O

O

N

O

HO

6


9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0

8.54

8.21

8.17

7.43

7.39

7.35

7.31

7.08

7.04

7.00

4.73

4.70

4.69

4.66

3.95

3.95

3.92

3.91

3.79

3.56

3.54

3.50

3.48

2.35

2.09

2.06

2.03

2.00

1.97

1.93

1.91

1.90

0.98

0.95

NHO

O

O

N

O

HO

10



S24

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0

CDCl3

1.23

1.27

1.30

1.88

1.95

1.97

2.01

2.04

2.07

2.32

2.36

3.50

3.53

3.56

3.58

3.77

4.12

4.16

4.19

4.23

4.63

4.66

4.67

4.70

6.98

7.01

7.05

7.26

7.33

7.37

7.41

8.14

8.19

8.49

NHO

O

O

N

O

HO

8


10 9 8 7 6 5 4 3 2 1

CDCl3

1.28

1.31

1.35

3.90

4.17

4.20

4.24

4.27

6.96

6.97

7.01

7.05

7.47

7.48

7.51

7.56

7.97

7.97

8.01

8.42

8.46

10.4

7


COOCH3

NH

OO

16


S25

11 10 9 8 7 6 5 4 3 2

1.97

2.09

2.13

2.27

2.31

2.41

2.44

2.51

3.66

3.69

3.70

3.72

3.75

4.90

4.93

4.94

4.97

7.30

7.33

7.37

7.37

7.53

7.56

7.56

7.57

7.59

8.34

8.38

9.04

10.6

3

NHO

O

N HN

O

Br

H

FF

F 4


11 10 9 8 7 6 5 4 3 2

CDCl3

1.86

1.91

1.94

1.97

2.01

2.03

2.28

2.31

3.56

3.59

3.62

3.66

3.73

4.61

4.63

4.65

4.67

7.09

7.13

7.41

7.43

7.44

7.46

7.49

7.90

7.91

7.94

7.95

8.53

8.57

10.3

2

NHO

O

N

O

HO

11



S26

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0

CDCl3

0.89

0.91

1.25

1.28

1.32

1.63

1.67

1.69

2.00

2.02

2.05

2.35

3.56

3.58

3.59

3.61

3.74

4.13

4.16

4.20

4.23

4.67

4.69

4.71

5.01

5.05

6.93

6.97

7.03

7.06

7.26

7.36

7.37

7.40

7.43

8.13

8.19

8.23

8.29

8.70

NHO

O

O

N

O

HO


9


S27

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30

Chloroform-d

25.1

028

.27

28.9

829

.61

50.5

3

60.6

6

77.0

080

.55

116.

0912

0.11

120.

7912

2.03

123.

8812

6.79

131.

0613

1.25

136.

7113

7.22

153.

09

169.

68

NHO

O

O

N HN

O

Br

H

13a

13C NMR (CDCl3/125MHz)

130 120 110 100 90 80 70 60 50 40 30

25.1

028

.26

28.9

9

50.5

3

60.6

6

120.

0912

0.77

122.

0212

6.78

131.

0613

1.23

NHO

O

O

N HN

O

Br

H

13a

DEPT-135 (CDCl3/125MHz)


S28

130 120 110 100 90 80 70 60 50 40 30

24.9

0

30.2

2

49.2

5

60.4

4

121.

4812

1.73

121.

9912

4.00

126.

8112

9.99

131.

88

NHO

O

N HN

O

Br

H

1


170 160 150 140 130 120 110 100 90 80 70 60 50 40 30

DMSO-d6

24.8

930

.22

39.7

0

49.2

5

60.4

4

115.

4312

1.49

121.

7312

1.98

123.

9912

6.81

128.

4612

9.99

131.

8713

5.04

167.

5116

8.97

171.

33

NHO

O

N HN

O

Br

H

1



S29

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

Chloroform-d

14.4

3

25.1

328

.96

50.6

6

60.8

561

.32

77.0

0

116.

2312

0.30

120.

8412

2.34

123.

9112

6.84

131.

2113

1.29

136.

4813

7.17

153.

89

169.

6916

9.78

NHO

O

O

N HN

O

Br

H

3


130 120 110 100 90 80 70 60 50 40 30 20

14.4

3

25.1

328

.95

50.6

5

60.8

561

.31

120.

3012

0.84

122.

3412

6.84

131.

2213

1.28

NHO

O

O

N HN

O

Br

H

3



S30

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

Chloroform-d

19.0

125

.04

27.9

429

.23

50.3

4

60.7

7

71.4

2

77.0

0

116.

1512

0.11

120.

8312

2.37

124.

1912

6.60

131.

2213

6.25

137.

15

154.

14

169.

4716

9.79

NHO

O

O

N HN

O

Br

H

5


130 120 110 100 90 80 70 60 50 40 30 20

19.0

2

25.0

427

.94

29.2

5

50.3

4

60.7

7

71.4

2

120.

0912

0.80

122.

3812

6.59

131.

0913

1.22

NHO

O

O

N HN

O

Br

H

5



S31

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30

171.

6417

1.32

168.

13

154.

6815

3.74

136.

5713

5.97

135.

2513

0.91

130.

5312

8.24

127.

9812

7.69

127.

0912

6.90

122.

5012

0.64

79.5

477

.00

66.7

366

.58

61.8

761

.06

58.7

149

.80

49.5

846

.78

46.3

831

.02

29.9

128

.84

28.1

027

.94

24.8

3

NHO

O

N

O

HO

N

O

OH

14

13C NMR (100 MHz, CDCl3)

130 120 110 100 90 80 70 60 50 40 30

131.

0812

8.40

128.

1412

7.85

127.

2412

7.04

122.

9512

2.65

120.

79

66.7

362

.02

61.2

258

.86

49.9

549

.59

46.9

546

.52

31.1

730

.05

28.9

928

.25

28.0

824

.99

NHO

O

N

O

HO

N

O

OH

14

DEPT-135 (100 MHz, CDCl3)


S32

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30

172.

1517

1.88

171.

8016

9.19

168.

9215

4.99

154.

20

136.

5513

6.02

131.

1213

0.52

127.

4712

6.84

123.

8612

3.59

123.

3412

2.87

122.

3812

0.88

80.1

479

.89

77.0

0

62.0

160

.96

60.1

050

.32

49.7

447

.02

46.7

031

.30

29.9

328

.90

28.2

125

.14

NHO

O

N

O

H HN

N

O

OH

2


130 120 110 100 90 80 70 60 50 40 30

131.

1312

7.47

126.

8312

6.63

123.

5912

3.34

122.

8712

2.43

120.

87

62.0

160

.93

60.0

9

50.3

349

.72

47.1

446

.68

28.2

126

.25

NHO

O

N

O

H HN

N

O

OH

2



S33

130 120 110 100 90 80 70 60 50 40 30

25.2

128

.17

29.2

3

49.9

152

.29

58.9

9

120.

0012

1.53

127.

1213

0.90

NHO

O

O

N

O

HO

6


170 160 150 140 130 120 110 100 90 80 70 60 50 40 30

Chloroform-d

25.2

028

.16

29.2

3

49.9

052

.28

58.9

9

77.0

080

.18

120.

0012

1.53

123.

2912

7.11

130.

89

137.

16

152.

89

168.

6717

2.42

NHO

O

O

N

O

HO

6



S34

130 120 110 100 90 80 70 60 50 40 30 20

19.0

0

25.2

427

.90

29.3

2

49.8

752

.46

59.0

2

71.2

5

120.

1212

1.99

127.

1013

1.06

NHO

O

O

N

O

HO

10


170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

Chloroform-d

18.9

925

.24

27.8

929

.32

49.8

752

.46

59.0

2

71.2

5

77.0

0

120.

1312

1.99

123.

6812

7.09

131.

0613

6.86

153.

98

168.

6917

2.57

NHO

O

O

N

O

HO

10



S35

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10

14.4

5

52.1

7

61.1

0

77.0

0

114.

3611

8.71

121.

34

130.

8013

4.52

141.

86

153.

62

168.

47

COOCH3

NH

OO

16


140 130 120 110 100 90 80 70 60 50 40 30 20 10

14.4

5

52.1

8

61.1

0

118.

7012

1.35

130.

7913

4.52

COOCH3

NH

OO

16



S36

170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10

Chloroform-d

14.3

8

25.2

029

.24

49.9

052

.36

59.0

061

.01

77.0

0

120.

0012

1.90

123.

4012

7.14

131.

0113

6.82

153.

70

168.

6117

2.42

NHO

O

O

N

O

HO

8


140 130 120 110 100 90 80 70 60 50 40 30 20 10

14.3

7

25.2

029

.24

49.9

152

.36

59.0

061

.01

120.

0012

1.89

127.

1313

1.01

NHO

O

O

N

O

HO

8



S37

80 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20

Chloroform-d

25.4

127

.81

51.2

5

61.0

4

77.0

0

116.

8012

1.20

125.

0812

8.14

131.

9213

4.56

136.

85

168.

7716

9.62

NHO

O

N HN

O

Br

H

FF

F 4


130 120 110 100 90 80 70 60 50 40 30 20

25.4

127

.82

51.2

5

61.0

4

121.

1912

2.36

125.

0812

8.14

131.

6813

1.90

NHO

O

N HN

O

Br

H

FF

F 4



S38

150 100 50 0

Chloroform-d

13.5

314

.44

18.7

919

.65

25.3

327

.14

27.9

129

.31

36.4

244

.80

47.9

349

.01

50.0

859

.50

61.0

3

77.0

080

.74

120.

0812

1.79

123.

2212

7.24

131.

1213

7.31

153.

80

168.

5917

2.27

NHO

O

O

N

O

HO

9


130 120 110 100 90 80 70 60 50 40 30 20 10

13.5

314

.44

18.7

919

.66

25.3

427

.13

27.9

129

.32

36.4

2

44.8

0

50.0

9

59.5

061

.03

80.7

5

120.

0812

1.79

127.

2413

1.13

NHO

O

O

N

O

HO

9



S39

0 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30

Chloroform-d

25.0

329

.03

31.1

836

.27

50.3

152

.08

59.1

3

77.0

0

121.

7112

2.64

123.

5512

7.17

127.

3612

8.41

131.

2013

1.65

134.

3313

7.24

162.

3516

5.22

168.

9817

2.18

NHO

O

N

O

HO

11


160 150 140 130 120 110 100 90 80 70 60 50 40 30

25.0

329

.03

31.1

936

.28

50.3

252

.09

59.1

3

121.

7212

2.66

127.

1812

7.37

128.

4213

1.21

131.

66

162.

36

NHO

O

N

O

HO

11



S40

Figure 1: COSY spectra of amide 1 (400MHz, CDCl3) Figure 2: Partial COSY spectra of amide 1 (400MHz, CDCl3): aromatic (a) and aliphatic regions (b).

ppm

2345678 ppm

2

3

4

5

6

7

8

9

ppm

2345 ppm

2

3

4

5

C9H

C9H

C12HC12’H

C10HC10’H &C20H

C11HC11’H

C12

HC

12’H

C10

HC

11H

C11

’H

C10’H &C20H

ppm

2345 ppm

2

3

4

5

C9H

C9H

C12HC12’H

C10HC10’H &C20H

C11HC11’H

C12

HC

12’H

C10

HC

11H

C11

’H

C10’H &C20H

ppm

2345 ppm

2

3

4

5

C9H

C9H

C12HC12’H

C10HC10’H &C20H

C11HC11’H

C12

HC

12’H

C10

HC

11H

C11

’H

C10’H &C20H

(a) C6Hppm

7.07.58.08.5 ppm

7.0

7.5

8.0

8.5

C4H C5HC7H

C15H, C19H, C16H & C18H

C4H

C5HC7H

C6HC15H, C19H, C16H & C18H

C6H

ppm

7.07.58.08.5 ppm

7.0

7.5

8.0

8.5

C4H C5HC7H

C15H, C19H, C16H & C18H

C4H

C5HC7H

C6HC15H, C19H, C16H & C18H

ppm

7.07.58.08.5 ppm

7.0

7.5

8.0

8.5

C4H C5HC7H

C15H, C19H, C16H & C18H

C4H

C5HC7H

C6HC15H, C19H, C16H & C18H

ppm

7.07.58.08.5 ppm

7.0

7.5

8.0

8.5

C4H C5HC7H

C15H, C19H, C16H & C18H

C4H

C5HC7H

C6HC15H, C19H, C16H & C18H

(b)


S41

Figure 3: Molecular structure of Compound 1 (amide) Figure 4: COSY spectra of amide 5 (400MHz, CDCl3)

NH

O

O

N

HN

OBr

1

2

34

5

6

7

8

9

1011

12 1314

1516

17

1819

20

NH2

NH1

ppm

123456789 ppm

2

4

6

8


S42

Figure 5: Partial COSY spectra of amide 5 (400MHz, C6D6): aromatic (a) and aliphatic regions (b). Figure 6: Molecular structure of Compound 5 (amide)

ppm

12345 ppm

2

3

4

5

C9H

C12

HC

12’HC

14H

C20H

C10

HC

10’H

C11

’H

C22H &C23H

C11

H

C21

H

C22H &C23H

C9H

C14H

C12’HC12H

C10HC10’H

C21H

C11HC20H

C11’H

ppm

12345 ppm

2

3

4

5

C9H

C12

HC

12’HC

14H

C20H

C10

HC

10’H

C11

’H

C22H &C23H

C11

H

C21

H

C22H &C23H

C9H

C14H

C12’HC12H

C10HC10’H

C21H

C11HC20H

C11’H

(a)

ppm

7.58.08.5 ppm

7.5

8.0

C4H

C4H

C6H

C6H

C5H

C5H

C7H

C7H

C15H & C19HC16H & C18H

C16H C18H

C15H C19H

ppm

7.58.08.5 ppm

7.5

8.0

C4H

C4H

C6H

C6H

C5H

C5H

C7H

C7H

C15H & C19HC16H & C18H

C16H C18H

C15H C19H

(b)

NH

OO

O

N

HN

OBr

1

2

34

5

6

7

8

9

1011

12 1314

1516

17

1819

20

NH2

21 22

23

NH1


S43

Figure 7: TOCSY spectra of amide 5 (400MHz, CDCl3) Figure 8: Partial TOCSY spectra of amide 5 (400MHz, CDCl3): aromatic (a) and aliphatic regions (b).

ppm

123456789 ppm

2

4

6

8

ppm

12345 ppm

2

3

4

5

C9H C12

HC

12’HC14

H C20H

C10

HC

10’H

C11

’H

C22H &C23H

C11

H

C21

H

C22H &C23H

C9H

C14H

C12’HC12H

C10HC10’H

C21H

C20HC11HC11H

ppm

12345 ppm

2

3

4

5

C9H C12

HC

12’HC14

H C20H

C10

HC

10’H

C11

’H

C22H &C23H

C11

H

C21

H

C22H &C23H

C9H

C14H

C12’HC12H

C10HC10’H

C21H

C20HC11HC11H

(b)

ppm

7.58.0 ppm

7.5

8.0

C4H

C4H

C6H

C6H

C5H

C5H

C7H

C7H

C15H & C19HC16H & C18H

C16H C18H

C15H C19H

ppm

7.58.0 ppm

7.5

8.0

C4H

C4H

C6H

C6H

C5H

C5H

C7H

C7H

C15H & C19HC16H & C18H

C16H C18H

C15H C19H

(a)


S44

Figure 9: COSY spectra of ester 6 (400MHz, CDCl3) Figure 10: Partial COSY spectra of ester 6 (400MHz, CDCl3): aromatic (a) and aliphatic regions (b).

ppm

2345678 ppm

2

3

4

5

6

7

8

ppm

234 ppm

2

3

4

5

C9H

C12

H

C10

HC12

’H

C14

H

C16H,C17H &C18H

C10

’H

C16H,C17H &C18H

C11

HC

11’H

C9H

C14H

C12’HC12H

C10HC10’HC11HC11’H

ppm

234 ppm

2

3

4

5

C9H

C12

H

C10

HC12

’H

C14

H

C16H,C17H &C18H

C10

’H

C16H,C17H &C18H

C11

HC

11’H

C9H

C14H

C12’HC12H


(b)

ppm

7.07.27.47.67.88.08.2 ppm

7.07.27.47.67.88.08.2

C4H C6H

C5H

C7H

C6H

C4H

C5HC7H

ppm

7.07.27.47.67.88.08.2 ppm

7.07.27.47.67.88.08.2

C4H C6H

C5H

C7H

C6H

C4H

C5HC7H

(a)


S45

Figure 11: Molecular structure of Compound 6 (ester) Figure 12: TOCSY spectra of ester 6 (400MHz, CDCl3)

NH

OO

O

N

O

O

1

2

34

5

6

7

8

9

1011

12 1314

15

1617

18

ppm

2345678 ppm

2

3

4

5

6

7

8


S46

Figure 13: Partial TOCSY spectra of ester 6 (400MHz, CDCl3): aromatic (a) and aliphatic regions (b). Figure 14: COSY spectra of ester 10 (400MHz, CDCl3):

ppm

7.27.47.67.88.08.2 ppm

7.07.27.47.67.88.08.2

C4HC6H

C6H

C4H

C7HC5H

C5H

C7H

ppm

7.27.47.67.88.08.2 ppm

7.07.27.47.67.88.08.2

C4HC6H

C6H

C4H

C7HC5H

C5H

C7H

(a)

ppm

2.03.04.0 ppm

2.0

3.0

4.0

C16H,C17H &C18H

C9H

C14H

C12’HC12H


C9H

C12

H

C10

HC12

’H

C14

H C16H, C17H & C18H

C10

’HC

11H

C11

’H

ppm

2.03.04.0 ppm

2.0

3.0

4.0

C16H,C17H &C18H

C9H

C14H

C12’HC12H


C9H

C12

H

C10

HC12

’H

C14

H C16H, C17H & C18H

C10

’HC

11H

C11

’H

(b)

ppm

12345678 ppm

2

3

4

5

6

7

8


S47

Figure 15: Partial COSY spectra of ester 10 (400MHz, CDCl3): aromatic (a) and aliphatic regions (b). Figure 16: Molecular structure of Compound 10 (ester)

ppm

7.07.27.47.67.88.08.2 ppm

7.0

7.2

7.4

7.6

7.8

8.0

8.2

C4HC6HC

7HC

5H

C4H

C6H

C7HC5H

ppm

7.07.27.47.67.88.08.2 ppm

7.0

7.2

7.4

7.6

7.8

8.0

8.2

C4HC6HC

7HC

5H

C4H

C6H

C7HC5H

(a)

ppm

1234 ppm

1

2

3

4

C17H &C18H

C9H

C15HC14H

C12’HC12H

C10HC10’HC16HC11H &

C11’H

C9H C

15H

C12

H

C10

H

C12

’H

C14H C17H &C18H

C10

’H

C11H & C11’H

C16Hppm

1234 ppm

1

2

3

4

C17H &C18H

C9H

C15HC14H

C12’HC12H

C10HC10’HC16HC11H &

C11’H

C9H C

15H

C12

H

C10

H

C12

’H

C14H C17H &C18H

C10

’H

C11H & C11’H

C16H

(b)

NH

OO

O

N

O

O

1

2

34

5

6

7

8

9

1011

12 1314

1516 17

18


S48

Figure 17: TOCSY spectra of ester 10 (400MHz, CDCl3): Figure 18: Partial TOCSY spectra of ester 10 (400MHz, CDCl3): aromatic (a) and aliphatic regions (b).

ppm

12345678 ppm

2

3

4

5

6

7

8

ppm

7.07.58.0 ppm

7.0

7.5

8.0

C4H

C6HC5H

C7H

C6H

C4H

C5HC7H

ppm

7.07.58.0 ppm

7.0

7.5

8.0

C4H

C6HC5H

C7H

C6H

C4H

C5HC7H

(a)

ppm

1234 ppm

1

2

3

4

C9H

C15

HC

12H

C10

H

C12

’HC

14H C17H &

C18H

C10

’H

C17H &C18H

C11H & C11’H

C16H

C9H

C15HC14H

C12’HC12H

C10HC10’H

C16HC11H &C11’H

ppm

1234 ppm

1

2

3

4

C9H

C15

HC

12H

C10

H

C12

’HC

14H C17H &

C18H

C10

’H

C17H &C18H

C11H & C11’H

C16H

C9H

C15HC14H

C12’HC12H

C10HC10’H

C16HC11H &C11’H

(b)


S49

Figure 19: NOESY spectra of amide 1 (400MHz, CDCl3) Figure 20: 2D NOESY extracts of amide 1 (400MHz, CDCl3)

ppm

23456789 ppm

2

3

4

5

6

7

8

9

ppm

9.39.49.5 ppm

2.2

2.4

NH2 NH1

C10’H

C12’H

C10H& C20H

NH2 vs C10H

NH1 vs C20H

ppm

9.39.49.5 ppm

2.2

2.4

NH2 NH1

C10’H

C12’H

C10H& C20H

ppm

9.39.49.5 ppm

2.2

2.4

NH2 NH1

C10’H

C12’H

C10H& C20H

NH2 vs C10H

NH1 vs C20H

C9H

ppm

9.39.49.5 ppm

4.95

5.00

5.05

NH2 NH1

NH2 vs C9H

C9H

ppm

9.39.49.5 ppm

4.95

5.00

5.05

NH2 NH1

NH2 vs C9H

ppm

9.39.49.5 ppm

4.95

5.00

5.05

NH2 NH1

NH2 vs C9H

ppm

9.259.30 ppm

3.5

3.6

3.7

NH1 vs C12H

NH1

C10H

C10’H

ppm

9.259.30 ppm

3.5

3.6

3.7

NH1 vs C12H

NH1

C10H

C10’H

NH1

C10H

C10’H

ppm

7.207.257.307.35 ppm

2.20

2.25

2.30

C20H

C4H C7HC19H

C20H vs C19H

C6H ppm

7.207.257.307.35 ppm

2.20

2.25

2.30

C20H

C4H C7HC19H

C20H vs C19H

ppm

7.207.257.307.35 ppm

2.20

2.25

2.30

C20H

C4H C7HC19H

C20H vs C19H

C20H

C4H C7HC19H

C20H vs C19H

C6H


S50

Figure 21: NOESY spectra of amide 5 (400MHz, CDCl3) Figure 22: 2D NOESY extracts of amide 5 (400MHz, CDCl3)

ppm

12345678 ppm

2

3

4

5

6

7

8

C19H C18H

C24H

C24H vs C19H

ppm

7.27.37.4 ppm

0.9

1.0

1.1C24H vs C18H

C19H C18H

C24H

C24H vs C19H

ppm

7.27.37.4 ppm

0.9

1.0

1.1

C19H C18H

C24H

C24H vs C19H

ppm

7.27.37.4 ppm

0.9

1.0

1.1C24H vs C18H

ppm

1234 ppm

8.6

8.8

NH1

C20

HC

12H

C21

H

C23

H

NH1 vs C20H

NH1 vs C12H

NH1 vs C21H

NH1 vs C23H

ppm

1234 ppm

8.6

8.8

NH1

C20

HC

12H

C21

H

C23

H

NH1 vs C20H

NH1 vs C12H

NH1 vs C21H

NH1 vs C23H

NH1

C20

HC

12H

C21

H

C23

H

NH1 vs C20H

NH1 vs C12H

NH1 vs C21H

NH1 vs C23H

C19H C18H

C19H C18H

C19H C18H


S51

Figure 23: NOESY spectra of ester 10 (400MHz, CDCl3) Figure 24: 2D NOESY extracts of ester 10 (400MHz, CDCl3)

ppm

12345678 ppm

2

3

4

5

6

7

8

C12’H

C12H

C5HC7Hppm

7.37.47.5 ppm

3.5

3.6

3.7C5H vs C12H

C12’H

C12H

C5HC7Hppm

7.37.47.5 ppm

3.5

3.6

3.7

C12’H

C12H

C5HC7Hppm

7.37.47.5 ppm

3.5

3.6

3.7C5H vs C12H

NH

C12H

C12’HNH vs C12H

ppm

8.48.58.68.7 ppm

3.5

3.6

3.7

NH

C12H

C12’HNH vs C12H

ppm

8.48.58.68.7 ppm

3.5

3.6

3.7


S52

Figure 25: NOESY spectra of ester 6 (400MHz, CDCl3) Figure 26: 2D NOESY extracts of amide 6 (400MHz, CDCl3)

ppm

3.83.94.0 ppm

1.5

1.6

C14H vs C17H

C14H

C17H

ppm

3.83.94.0 ppm

1.5

1.6

C14H vs C17H

C14H

C17H

ppm

2345678 ppm

2

3

4

5

6

7

8

C12H

C12’H

C5H vs C12H

ppm

7.37.4 ppm

3.5

3.6

3.7

C5HC7H

C12H

C12’H

C5H vs C12H

ppm

7.37.4 ppm

3.5

3.6

3.7

C12H

C12’H

C5H vs C12H

ppm

7.37.4 ppm

3.5

3.6

3.7

C5HC7H

C16H

NH

NH vs C16H

ppm

8.38.4 ppm

1.4

1.5

1.6

C16H

NH

NH vs C16H

ppm

8.38.4 ppm

1.4

1.5

1.6

NH

C12H

C12’H

NH vs C12H

ppm

8.38.4 ppm

3.5

3.6

3.7

NH

C12H

C12’H

NH vs C12H

ppm

8.38.4 ppm

3.5

3.6

3.7

C5HC7H

C9H

C5H vs C9H

ppm

7.37.4 ppm

4.6

4.7

4.8

C5HC7H

C9H

C5H vs C9H

ppm

7.37.4 ppm

4.6

4.7

4.8


S53

No: VDMSO-d6 (in µ lit)

δNH2 δNH1

1 0 9.15 9.15 2 5 9.36 9.18 3 10 9.48 9.2 4 15 9.57 9.21 5 20 9.63 9.21 6 25 9.67 9.22 7 30 9.71 9.21 8 35 9.73 9.21 9 40 9.75 9.2 10 45 9.77 9.19 11 50 9.77 9.18

Figure 27: Titration study of 1 in CDCl3 (5 mmol) with DMSO-d6 (Volume of DMSO-d6 added at each addition = 5 µl)

0 10 20 30 40 509.1

9.2

9.3

9.4

9.5

9.6

9.7

9.8

9.9

Chem

ical

Shi

ft (p

pm)

Volume of DMSO-d6 (in microlitres)

NH2 NH1

NH1

NH2

NH1

NH2


S54


δNH2 δNH1 Concentration in mMs

1 0 9.19 8.47 2 2 5 9.34 8.55 1.9802 3 10 9.42 8.59 1.9608 4 15 9.48 8.62 1.9418 5 20 9.54 8.64 1.9231 6 25 9.58 8.66 1.9048 7 30 9.6 8.66 1.8868 8 35 9.62 8.66 1.8692 9 40 9.64 8.66 1.8519 10 45 9.65 8.65 1.8349 11 50 9.66 8.65 1.8182


0 10 20 30 40 50

8.5

8.6

8.7

8.8

8.9

9.0

9.1

9.2

9.3

9.4

9.5

9.6

9.7

Chem

ical

Shi

ft (p

pm)

Volume of DMSO-d6

NH2 NH1

NH2

NH1

NH2

NH1


S55


δNH Concentration in mM

1 0 8.55 2 2 5 8.53 1.9802 3 10 8.51 1.9608 4 15 8.49 1.9418 5 20 8.47 1.9231 6 25 8.45 1.9048 7 30 8.43 1.8868 8 35 8.41 1.8692 9 40 8.39 1.8519 10 45 8.38 1.8349 11 50 8.36 1.8182


-5 0 5 10 15 20 25 30 35 40 45 50 558.0

8.2

8.4

8.6

8.8

9.0

9.2

9.4

9.6

9.8

10.0

Chem

ical

Shi

ft (p

pm)

Volume of DMSO-d6 (microlitres)

NH

NHNH


S56

Crystal Data Table 1: Hydrogen bonding Parameters

Compound

No.

Tortion angles (Deg,) Hydrogen bonding Parameters Ant Pro Distances (Å) Angles (Deg.)

φ ψ φ ψ O...H N...O C=O..N NH..O

Amides 1

173.40

-65.37

-55.97

164.59

2.173

3.025

127.28

170.80 2 170.23 -69.58 -60.64 174.04 2.030 2.881 131.10 169.81 3 -172.38 -70.08 -58.82 164.32 2.259 3.075 123.31 158.34 4 176.23 -72.66 -55.94 166.62 2.108 2.960 132.15 171.33 5 166.51 -71.89 -56.49 162.41 2.178 3.033 127.17 172.17

Esters 6

153.97

150.75

-61.60

-139.47

5.263

5.842

65.58

128.93 7 -177.80 140.07 -69.70 153.71 5.452 5.930 72.70 120.03 8 -144.62 146.41 -57.70 135.55 5.237 5.790 64.08 125.28 9 167.51 -144.35 -56.68 -38.27 4.737 5.552 48.65 156.00

10 -138.63 146.28 -59.04 134.8 5.366 5.874 62.70 122.65 11 -177.28 -130.50 -59.62 156.72 3.177 4.510 111.12 148.44

Crystal Data Table 2: Potential Hydrogen bonding parameters

=============================================================== Analysis of Potential Hydrogen Bonds for Compound 1

=============================================================== Donor --- H....Acceptor D - H H...A D...A D - H...A ============================================================== 1 C(12A) --H(12A) ..O(1) Inter 0.97 2.649 3.452 140 2 C(11A) --H(11A) ..N(1) Inter 0.97 2.705 3.453 134 3 N(3) --H(3) ..O(2) Inter 0.86 2.038 2.877 165 4 N(1) --H(1) ..O(3) Intra 0.86 2.173 3.025 170 ==============================================================

Analysis of Potential Hydrogen Bonds for Compound 2 =============================================================== Donor --- H....Acceptor D - H H...A D...A D - H...A =============================================================== 1 C(23) --H(23B) ..N(1) Inter 0.96 2.72 3.556 145 2 C(5) --H(5A) ..O(3) Inter 0.97 2.37 3.169 138 3 N(4) --H(4) ..O(3) Inter 0.86 2.06 2.859 154 4 N(2) --H(2) ..O(5) Intra 0.93 2.03 2.881 170 ===============================================================

Analysis of Potential Hydrogen Bonds for Compound 3 Donor --- H....Acceptor D - H H...A D...A D - H...A =============================================================== 1 C(21) --H(21B) ..O(1) intra 0.96 2.65 3.606 173 2 N(1) --H(1) ..O(4) Intra 0.86 2.26 3.075 158 3 C(9) --H(9) ..O(3) inter 0.98 2.63 3.178 115 4 N(3) –H(3) ..O(3)Intra 0.86 2.08 2.911 161 ===============================================================


S57

Analysis of Potential Hydrogen Bonds for Compound 4 =============================================================== Donor --- H....Acceptor D - H H...A D...A D - H...A =============================================================== 1C(20) --F(3) ..O(1)Halogen bonding 1.334 2.898 3.607 111 2 N(1) --H(1) ..O(3) intra 0.86 2.108 2.960 171 3 C(12) --H(12A) ..O(1) inter 0.97 2.529 3.447 158 4 N(3) --H(3) ..O(2) Inter 0.86 2.020 2.857 164 5 C(27) --Br(1) ..F(3) Halogen bonding 1.895 3.020 4.867 163 ===============================================================

Analysis of Potential Hydrogen Bonds for Compound 5 =============================================================== Donor --- H....Acceptor D - H H...A D...A D - H...A =============================================================== 1 N(1) --H(1) ..O(3) Intra 0.86 2.17 3.033 172 2 C(9) --H(9) ..O(2) inter 0.98 2.63 3.193 116 3 C(12) --H(12B) ..O(1) inter 0.97 2.32 3.140 141 4 N(3) --H(3) ..O(2) Inter 0.86 2.06 2.87 157 ===============================================================

Analysis of Potential Hydrogen Bonds for Compound 6 Donor --- H....Acceptor D - H H...A D...A D - H...A =============================================================== 1 C(6) --H(6) ..O(1) Inter 0.93 2.53 3.425 160 2 C(4) --H(4) ..O(3) Inter 0.93 2.71 3.551 150 3 C(11) –H(11A) ..O(5) inter 0.97 2.71 3.623 158 4 C(12) –H(12B) ..O(2) inter 0.97 2.29 3.351 136 5 C(14) --H(14A) ..O(3) Inter 0.96 3.15 3.205 84 6 C(14) --H(14B) ..O(3) Inter 0.96 2.84 3.205 103 7 C(14) --H(14C) ..O(3) Inter 0.96 3.09 3.205 88 8 N(1) --H(1) ..O(3) Intra 0.86 2.02 2.685 133 ===============================================================

Analysis of Potential Hydrogen Bonds for Compound 7 Donor --- H....Acceptor D - H H...A D...A D - H...A =============================================================== 1 C(5) --H(5) ..O(2) 0.93 2.68 3.416 137 2 C(20) --H(20) ..O(3) Intra 0.93 2.74 3.641 163 3 N(1) --H(1) ..O(3) Intra 0.86 2.17 2.806 131 ===============================================================

Analysis of Potential Hydrogen Bonds for Compound 8 =============================================================== Donor --- H....Acceptor D - H H...A D...A D - H...A ============================================================== 1 C(16) --H(16B) ..O(3) Inter 0.98 2.63 3.577 163 2 C(6) --H(6) ..O(1) Inter 0.95 2.35 3.291 151


S58

3 C(4) --H(4) ..O(3) Inter 0.95 2.46 3.322 174 4 C(11) --H(11A) ..O(5) Inter 0.99 2.65 3.533 148 5 C(12) --H(12A) ..O(3) Inter 0.99 2.65 3.623 165 6 C(12) --H(12B) ..O(2) Inter 0.99 2.46 3.285 141 7 C(14) --H(14A) ..O(3) Inter 0.98 3.16 3.152 81 8 C(14) --H(14B) ..O(3) Inter 0.98 2.76 3.152 105 9 C(14) --H(14C) ..O(3) Inter 0.98 3.02 3.152 105 10 N(1) --H(1) ..O(2) Intra 0.88 2.07 2.681 126 ==============================================================

Analysis of Potential Hydrogen Bonds for Compound 9 =============================================================== Donor --- H....Acceptor D - H H...A D...A D - H...A =============================================================== 1 C(25) --H(25C) ..O(3) Inter 0.98 2.51 3.346 143 2 C(4) --H(4) ..O(2) Inter 0.95 2.38 3.284 158 3 C(23) --H(23B) ..O(1) Inter 0.98 2.60 3.468 148 4 C(15) --H(15A) ..O(2) Inter 0.99 2.65 3.938 145 5 C(18) --H(18B) ..O(4) Intra 0.99 2.41 2.818 104 6 C(14) --H(14) ..O(3) Intra 1.00 2.50 2.691 90 7 C(17) --H(17A) ..O(5) Intra 0.99 2.62 3.432 139 8 N(1) --H(1) ..O(2) Intra 0.88 2.02 2.711 134 ===============================================================

Analysis of Potential Hydrogen Bonds for Compound 10 Donor --- H....Acceptor D - H H...A D...A D - H...A =============================================================== 1 C(12) --H(12A) ..O(3) inter 0.97 2.67 3.634 171 2 C(12) --H(12B) ..O(2) Inter 0.97 2.64 3.382 133 3 N(1) –H(1) ..O(2)Intra 0.86 2.14 2.710 123 ===============================================================

Analysis of Potential Hydrogen Bonds for Compound 11 =============================================================== Donor --- H....Acceptor D - H H...A D...A D - H...A =============================================================== 1C(17) --H(17) ..O(4)inter 0.93 2.668 3.488 148 2C(16) --H(16) ..O(3)intra 0.93 2.589 3.486 162 3 N(1) --H(1) ..O(3) Intra 0.86 3.177 3.936 148 4 N(1) --H(1) ..O(2) Intra 0.86 2.185 2.798 128 5 C(5) --H(5) ..O(1) inter 0.93 2.634 3.367 136 ===============================================================


S59

Single Crystal X-ray Crystallographic Data.

Crystal Data for the compounds 1-11 were collected at T = 293 K, on SMART APEX CCD Single Crystal X-ray diffractometer using Mo KR radiation (λ ) 0.7107 Å). The structures were solved by direct methods using SHELXTL. All the data were corrected for Lorentz polarization and absorption effects. SHELX-97 (ShelxTL) was used for structure solution and full matrix least-squares refinement on F2. Hydrogen atoms were included in the refinement in the riding mode. The refinements were carried out using SHELXL-97.4 Crystal Data for 1. Single crystals of 1 were grown by slow evaporation of the mixture of methanol and dichloromethane. Colorless prism crystals of approximate size 0.31 x 0.21 x 0.12 mm, was used for data collection. Temperature = 297 K, Wave length = 0.71073 Å, Hemisphere acquisition. Total scans = 4, F(000) = 440, θ range = 1.90 to 25.00, completeness to θ of 25.00º is 99.6 %, SADABS correction applied, Goodness-of-fit on F2 = 0.990, C20H20Br N3O3, M = 430.30. Crystals belong to Monoclinic, space group P21, a = 11.1418(8), b = 7.1748(5), c = 12.9148(10) Å, V = 994.55(13) Å3, Z = 2, Dc = 1.437 mg m-3, µ (Mo-Kα) = 2.091 mm-1, 5062 reflections measured, 2888 unique [I>2σ(I)], R value 0.0297, wR2 = 0.0714. Crystal Data for 2. Single crystals of 2 were grown by slow evaporation of the mixture of ethyl acetate and pet. ether. Colorless needle of approximate size 0.17 x 0.12 x 0.12 mm, was used for data collection. Temperature = 295 K, Wave length = 0.71073 Å, Hemisphere acquisition. Total scans = 3, F(000) = 952, θ range = 2.11 to 24.99º, completeness to θ of 24.99º is 100.0 %. SADABS correction applied, Goodness-of-fit on F2 = 0.999 C23H32N4O5, M = 444.53. Crystals belong to Orthorhombic, space group P212121, a = 8.9732 (8), b = 10.4292 (9), c = 25.653 (2) Å, V = 2400.7 (4) Å3, Z = 4, Dc = 1.230 mg m-3, µ (Mo-Kα) = 0.088 mm-1, 12181 reflections measured, 4239 unique [I>2σ(I)], R value 0.0467, wR2 = 0.1223. Crystal Data for 3. Single crystals of 3 were grown by slow evaporation of the mixture of methanol and dichloromethane. Colorless plate of approximate size 0.17 x 0.12 x 0.02 mm, was used for data collection. Temperature = 296 K, Wave length = 0.71073 Å, Total scans = 4, F(000) = 944, θ range = 1.62 to 25.00º, completeness to θ of 24.99º is 100.0 %. SADABS correction applied, Goodness-of-fit on F2 = 1.203, C21H22BrN3O4, M = 460.33. Crystals belong to Orthorhombic, space group P212121, a = 7.1599(7), b = 11.8460(11), c = 25.160(2) Å, V = 2134.0(4) Å3, Z = 4, Dc = 1.433 mg m-3, µ (Mo-Kα) = 1.958 mm-1, 17385 reflections measured, 3754 unique [I>2σ(I)], R value 0.0749, wR2 = 0.1330. Crystal Data for 4. Single crystals of 4 were grown by slow evaporation of the mixture of methanol. Colorless thin plate of approximate size 0.48 x 0.14 x 0.02 mm, was used for data collection. Temperature = 297 K, Wave length = 0.71073 Å, Total scans = 4, F(000) = 488, θ range = 1.89 to 25.00º, completeness to θ of 25.00º is 99.7 %. SADABS correction applied, Goodness-of-fit on F2 = 0.985, C20H17BrF3N3O3, M = 484.28. Crystals belong to monoclinic, space group P21, a = 11.016(5), b = 7.612(3), c = 12.920(5) Å, V = 1059.2(7) Å3, Z = 2, Dc = 1.518 mg m-3, µ (Mo-Kα) = 1.992 mm-1, 5304 reflections measured, 3754 unique [I>2σ(I)], R value 0.0469, wR2 = 0.0954.


S60

Crystal Data for 5. Single crystals of 5 were grown by slow evaporation of the mixture of methanol. Colorless needle of approximate size 0.62 x 0.15 x 0.11 mm, was used for data collection. Temperature = 297 K, Wave length = 0.71073 Å, Total scans = 4, F(000) = 504, θ range = 2.19 to 25.00º, completeness to θ of 25.00º is 98.7 %. SADABS correction applied, Goodness-of-fit on F2 = 1.203, C23H26BrN3O4, M = 488.38. Crystals belong to monoclinic, space group P21, a = 12.8420(19), b = 7.0231(10), c = 13.3863(19) Å, V = 1207.3(3) Å3, Z = 2, Dc = 1.343 mg m-3, µ (Mo-Kα) = 1.734 mm-1, 9259 reflections measured, 4152 unique [I>2σ(I)], R value 0.1045, wR2 = 0.1533. Crystal Data for 6. Single crystals of 6 were grown by slow evaporation of the mixture of methanol and dichloromethane. Colorless needle of approximate size 1.37 x 0.54 x 0.47 mm, was used for data collection. Temperature = 297 K, Wave length = 0.71073 Å, Total scans = 4, F(000) = 744, θ range = 2.28 to 25.00º, completeness to θ of 25.00º is 99.8 %. SADABS correction applied, Goodness-of-fit on F2 = 1.042, C18H24N2O5, M = 348.39. Crystals belong to orthorhombic, space group P2(1)2(1)2(1), a = 8.547(5), b = 9.694(5), c = 22.943(12) Å,. V = 1900.9(18) Å3, Z = 4, Dc = 1.217 mg m-3, µ (Mo-Kα) = 0.089 mm-1, 18354 reflections measured, 3348 unique [I>2σ(I)], R value 0.0479, wR2 = 0.1257. Crystal Data for 7. Single crystals of 7 were grown by slow evaporation of the mixture of ethylacetate and pet. ether. Colorless rectangular crystals of approximate size 0.43 x 0.31 x 0.14 mm, was used for data collection. Temperature = 296 K, Wave length = 0.71073 Å, Total scans = 4, F(000) = 904, θ range = 2.09 to 25.00º, completeness to θ of 25.00º is 100 %. SADABS correction applied, Goodness-of-fit on F2 = 1.066, C24H28N2O5, M = 424.48. Crystals belong to orthorhombic, space group P2(1)2(1)2(1), a = 10.6231(7), b = 10.9569(7), c = 19.5280(12) Å, V = 2273.0(3) Å3, Z = 4, Dc = 1.240 mg m-3, µ (Mo-Kα) = 0.087 mm-1, 11578 reflections measured, 4004 unique [I>2σ(I)], R value 0.0402, wR2 = 0.0946. Crystal Data for 8. Single crystals of 8 were grown by slow evaporation of the mixture of ethylacetate and pet. ether. Colorless thick plate crystals of approximate size 0.50 x 0.27 x 0.22 mm, was used for data collection. Temperature = 173 K, Wave length = 0.71073 Å, Total scans = 4, F(000) = 680, θ range = 2.318 to 28.349º, completeness to θ of 28.41º is 99.1 %. SADABS correction applied, Goodness-of-fit on F2 = 1.031, C16H20N2O5, M = 320.34. Crystals belong to orthorhombic, space group P2(1)2(1)2(1), a = 8.111(2), b = 9.756(2), c = 20.126(6) Å, V = 1592.6(7) Å3, Z = 4, Dc = 1.336 mg m-3, µ (Mo-Kα) = 0.100 mm-1, 8457 reflections measured, 3901 unique [I>2s(I)], R value 0.0353, wR2 = 0.0823. Crystal Data for 9. Single crystals of 9 were grown by slow evaporation of the mixture of ethylacetate and pet. ether. Colorless block crystals of approximate size 0.62 x 0.59 x 0.27 mm, was used for data collection. Temperature = 100 K, Wave length = 0.71073 Å, Total scans = 4, F(000) = 952, θ range = 2.10 to 25.00º, completeness to θ of 25.00º is 99.8 %. SADABS correction applied, Goodness-of-fit on F2 = 1.090, C25H34N2O5, M = 442.54. Crystals belong to orthorhombic, space group P2(1)2(1)2(1), a = 7.4115(4), b = 16.5480(9), c = 19.3577(11) Å, V = 2374.1(2) Å3, Z = 4, Dc = 1.238 mg m-3, µ (Mo-Kα) = 0.086 mm-1, 17494 reflections measured, 4176 unique [I>2σ(I)], R value 0.0442, wR2 = 0.1054.


S61

Crystal Data for 10. Single crystals of 10 were grown by slow evaporation of the mixture of ethylacetate and pet. ether. Colorless plate crystals of approximate size 0.44 x 0.34 x 0.14 mm, was used for data collection. Temperature =

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