A palladium-catalyzed domino reaction as key step for the synthesis of functionalized aromatic amino acids

Article abstract of DOI:10.1055/s-0033-1339892

A variety of substituted aromatic systems are synthesized by the Catellani reaction. These are used as precursors for novel amino acids with a basic side chain. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339892

Accounts and
Rapid Communications in
Synthetic Organic Chemistry
SYNLETT
SUPPORTING INFORMATION
Supporting Information
for DOI: 10.1055/s-0033-1339892
©
Georg Thieme Verlag KG Stuttgart · New York 2013
Thieme

A Palladium Catalyzed Domino Reaction as Key Step for
WKHꢀ6\QWKHVLVꢀRIꢀFunctionalized Aromatic Amino Acids
Supporting Information
a
a,b
a
b
Tina Stark, Marcel Suhartono, Michael W. Göbel,* Mark Lautens*
a
Institute of Organic Chemistry and Chemical Biology, Goethe University, Max-von-Laue-
Straße 7, 60438 Frankfurt am Main, Germany
b
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St.
George Street, Toronto, Ontario M5S 3H6, Canada
m.goebel@chemie.uni-frankfurt.de; mlautens@chem.utoronto.ca
General information
2
Experimental section
NMR spectra
2
24
66
68
ee Determination and HPLC chromatograms
References
1
ꢀ

General Information:
1
13
13
19
NMR: Bruker DPX 250 ( H: 250 MHz; C: 63 MHz), Bruker AM 300 ( C: 75 MHz; F:
1
1
2
82 MHz) or Bruker Avance 400 ( H: 400 MHz); H chemical shifts (G) are given in ppm
relative to CDCl (7.26 ppm) as internal standard; multiplicities are indicated as s for singlet,
d-doublet, dd-doublet of doublets, t-triplet, q-quartet, m-multiplet, br s-broad singlet, denotes
3
*
1
1
13
rotamer signals; if necessary, H, H-COSY spectra were used for proton assignment;
C
chemical shifts (G) are reported with proton decoupling in ppm relative to CDCl (77.0 ppm)
3
19
as internal standard; F chemical shifts (G) are reported with decoupling in ppm. FT-IR:
-
1
Perkin-Elmer 1600 series or Perkin-Elmer Spectrum Two; peaks are reported in cm ;
intensities are classified as strong (s), medium (m) or weak (w). Melting points (uncorrected):
Kofler hot-plate microscope. Optical rotation: Perkin-Elmer polarimeter 241 with thermostats
T
D
°C
Haake G and Haake D8; values are given as follows [D]
(c = g/100 mL, solvent).
Elementary analysis: Elementar vario micro cube; values are given in %. Mass spectrometry:
Fisons VG Platform II (ESI); values are given as follows m/z ratio (intensity in %). High-
resolution mass spectrometry (HRMS): MALDI Orbitrap XL (Thermo Fisher Scientific); values
are given as m/z ratios. Analytical thin layer chromatography (TLC): alumina plates
precoated with silica gel 60 F254 indicator (EMD); spots were visualized by UV light (254 nm).
Flash column chromatography: Silica gel 60 (0.04 – 0.063 mm; Macherey-Nagel).
Enantiomeric excesses were determined by HPLC analysis using analytical chiral columns
from Daicel Chemical Industries Ltd (Chiralpak IA). Triphenylphosphine was recrystallized
from EtOH. All other reagents were obtained from commercial suppliers and were used
without further purification. 2,4,6-Triisopropylbenzenesulfonyl azide (tris-azide) was
[1]
synthesized according to literature.
Experimental section:
[
2]
1
-Iodo-2-phenylbenzene (1e)
2
2
-Aminobiphenyl (2.00 g; 11.8 mmol) was suspended in H
.4 mL) was added. After slow addition of a solution of NaNO
2
O (12 mL) at 0 °C and HCl (12 M;
2
(978 mg; 14.2 mmol) in H O
2
(
2
3 mL) the reaction mixture was stirred for 45 min at 0 °C. A solution of ice cooled KI (3.90 g;
3.5 mmol) in H O (3 mL) was added and the reaction mixture was allowed to warm to room
2
temperature overnight.
The reaction mixture was extracted with Et
2
O (4x) and the organic layers were washed with a
HCl solution (3 M), saturated NaHCO
3
, saturated Na , and brine. After drying over
2 2 5
S O
MgSO4 and concentration in vacuo the crude product was purified by column
chromatography (pure n-hexane). A colourless oil (3.07 g; 93%) was obtained.
1
3
H NMR (250 MHz, CDCl ): 7.96 (dd, J = 0.8 Hz, 8 Hz, 1H, aryl-H), 7.44 – 7.29 (m, 7H, aryl-
13
H), 7.04 (m, 1H, aryl-H). C NMR (63 MHz, CDCl
28.7, 128.1, 127.9, 127.6, 98.6. IR (neat): 3056 (m), 1578 (w), 1525 (m), 1460 (s), 1426
m), 1351 (w), 1294 (w), 1251 (w), 1159 (w), 1114 (w), 1072 (m), 1017 (s), 1004 (s), 915 (w),
3
): 146.7, 144.2, 139.5, 130.1, 129.3,
1
(
2
ꢀ
ꢀ

8
58 (w), 746 (s), 699 (s), 648 (s). R (n-hexane/EtOAc, 25:1) = 0.75. Elementary analysis:
f
calcd for C H I (280.10): C 51.46, H 3.24; found C 51.60, H 3.36.
12
9
General procedure for the conversion of aryl bromides to aryl iodides (1f, 1h, 1i); GP1:
Aryl bromide (10 mmol) was dissolved in dry THF (30 mL) and cooled to -78 °C under an
argon atmosphere. n-Butyllithium (1.6 M in n-hexane; 7.5 mL; 12 mmol) was added
dropwise. After 15 minutes a solution of I (3.81 g; 15 mmol) in dry THF (10 mL) was added
2
and the reaction mixture was allowed to warm to room temperature overnight.
For workup the reaction mixture was concentrated in vacuo. H
and it was extracted with DCM (3x). The combined organic phases were washed with
saturated Na solution and H O. After drying over MgSO and concentration under
reduced pressure, the crude product was purified by column chromatography.
2
O was added to the residue
S O
2 2 5
2
4
1
-Iodonaphthalene (1f)
Eluent for column chromatography: n-hexane/EtOAc, 50:1.
Yield: 2.16 g (85%); colourless oil.
1
3
H NMR (250 MHz, CDCl ): 8.11 - 8.08 (m, 2H, aryl-H), 7.86 – 7.76 (m, 2H, aryl-H), 7.62 –
13
7
1
.49 (m, 2H, aryl-H), 7.19 (t, J = 8 Hz, 1H, aryl-H). C NMR (63 MHz, CDCl ): 137.4, 134.4,
3
34.1, 132.1, 129.0, 128.5, 127.7, 126.8, 126.7, 99.5. IR (neat): 3052 (w), 2375 (w), 1555
(
(
m), 1499 (s), 1374 (m), 1251 (m), 1200 (m), 1130 (w), 1022 (w), 944 (s), 788 (s), 763 (s). R
f
7
n-hexane/EtOAc, 25:1) = 0.75. Elementary analysis: calcd for C10H I (254.07): C 47.27,
H 2.78; found C 47.55, H 2.90.
9
-Iodophenanthrene (1h)
Eluent for column chromatography: n-hexane/EtOAc, 50:1.
Yield: 2.59 g (85%); colourless solid after recrystallization from DCM/n-hexane.
1
3
H NMR (250 MHz, CDCl ): 8.68 – 8.62 (m, 2H, aryl-H), 8.45 (s, 1H, aryl-H), 8.23 (m, 1H,
13
aryl-H), 7.79 – 7.56 (m, 5H, aryl-H). C NMR (63 MHz, CDCl ): 138.6, 133.3, 133.0, 132.1,
3
1
1
30.7, 130.4, 127.8, 127.6, 127.5, 127.3, 127.1, 122.81, 122.75, 98.7. IR (KBr): 1488 (w),
445 (w), 1366 (w), 1186 (w), 952 (w), 901 (w), 879 (m), 845 (m), 744 (s), 719 (s), 616 (w).
[
3]
mp: 89 – 91 °C (lit: 91 – 92 °C ). R (n-hexane/EtOAc, 25:1) = 0.70. HRMS: calcd for C14H I
f 9
+
[M] 303.9743; found 303.9744.
1
-Iodopyrene (1i)
Eluent for column chromatography: n-hexane/EtOAc, 50:1.
Yield: 2.85 g (87%); light yellow solid after recrystallization from MeCN.
3
ꢀ
ꢀ

1
H NMR (250 MHz, CDCl
3
): 8.50 (m, 1H, aryl-H), 8.32 – 8.00 (m, 7H, aryl-H), 7.88 (m, 1H,
13
aryl-H). C NMR (63 MHz, CDCl ): 136.8, 132.6, 131.4, 131.07, 131.05, 131.0, 129.4, 128.0,
3
1
27.1, 126.5, 126.0, 125.8, 125.6, 125.5, 124.0, 96.2. IR (KBr): 3029 (w), 1584 (m), 1480
(
(
w), 1451 (w), 1425 (m), 1310 (w), 1240 (w), 1200 (w), 1176 (w), 1077 (w), 1006 (m), 963
[
4]
f
m), 835 (s), 812 (m), 750 (m), 705 (s), 671 (m). mp: 85 – 87 °C (lit: 85 – 87 °C ). R (n-
+
hexane/EtOAc, 25:1) = 0.65. HRMS: calcd for C H I [M] 327.9743: found 327.9741.
16
9
Anthracen-1-yl trifluoromethanesulfonate (1g)
-Anthracenol (390 mg; 2.0 mmol) was dissolved in dry DCM (10 mL). After addition of
1
pyridine (322 μL; 4.0 mmol) the brown solution was cooled to 0 °C and a solution of triflic
anhydride (404 μL; 2.4 mmol) in dry DCM (4 mL) was added dropwise. The reaction mixture
was stirred at room temperature for 1 h. Then, the reaction was quenched by addition of
diluted HCl. After washing once with saturated NaHCO
3
solution and brine the organic phase
was dried over MgSO and purified by column chromatography (cyclohexane/EtOAc, 50:1).
4
The product was directly used for the next step.
Yield: 587 mg (90%); yellow oil.
1
3
H NMR (250 MHz, CDCl ): 8.65 (m, 1H, aryl-H), 8.48 (m, 1H, aryl-H), 8.13 – 7.98 (m, 3H,
13
aryl-H), 7.63 – 7.52 (m, 2H, aryl-H), 7.50 – 7.38 (m, 2H, aryl-H). C NMR (63 MHz, CDCl
3
):
1
1
45.9, 132.5, 132.4, 132.3, 128.9, 128.7, 128.0, 127.0, 126.7, 124.7, 123.7, 122.1, 121.8,
21.4, 120.0, 116.8. F NMR (282 MHz, CDCl ): - 73.3.
3
19
[
5]
3
-Iodo-1-[(4-methylbenzene)sulfonyl]-1H-indole (1j)
Indole (4.0 g; 34.1 mmol) and KOH (4.78 g; 85.3 mmol) were dissolved in DMF (60 mL).
After dropwise addition of a solution of I (8.73 g; 34.4 mmol) in DMF (60 mL) the brown
2
solution was stirred at room temperature for 30 min. KOH (4.78 g; 85.3 mmol) and
tosylchloride (13.65 g; 71.6 mmol) were added and the stirring was continued overnight.
H
2
O was added to the reaction mixture and it was extracted with Et
2
O (3x). The combined
. After
organic layers were washed with H O and brine before drying over MgSO
2
4
concentration to dryness the crude product was crystallized from n-hexane. A light yellow
solid (8.07 g; 60%) was obtained.
1
3
H NMR (250 MHz, CDCl ): 7.96 (m, 1H, aryl-H), 7.78 (d, J = 8.5 Hz, 2H, aryl-H), 7.70 (s, 1H,
13
aryl-H), 7.40 – 7.30 (m, 3H, aryl-H), 7.26 – 7.22 (m, 2H, aryl-H), 2.35 (s, 3H, CH
3
). C NMR
): 145.3, 135.0, 134.4, 132.4, 130.0, 129.8, 126.9, 125.6, 123.9, 122.0,
13.4, 66.8, 21.6. IR (KBr): 3119 (m), 1592 (m), 1438 (m), 1370 (s), 1267 (m), 1171 (s), 1125
(
63 MHz, CDCl
3
1
(
1
s), 1086 (s), 1017 (s), 920 (m), 803 (m), 753 (m), 688 (s), 653 (s), 574 (s), 532 (s). mp:
31 – 133 °C (lit: 131- 133 °C ). R (n-hexane/EtOAc, 25:1) = 0.30. Elementary analysis:
f
[
5]
calcd for C H INO S (397.23): C 45.35, H 3.04, N 3.53, S 8.07; found: C 45.32, H 3.09,
15
12
2
N 3.44, S 7.80.
4
ꢀ
ꢀ

General procedure for the Catellani reaction (2a-j); GP2:
Pd(OAc) (45 mg; 0.2 mmol) and triphenylphosphine (115 mg; 0.44 mmol) were filled into an
2
oven dried sealable tube and dissolved in dry MeCN (12 mL) under argon atmosphere. After
5
2
min Cs
2 3
CO (3.26 g; 10 mmol), the aryl iodide (2 mmol), 1,3-dibromopropane (2.04 mL;
0 mmol; for iodobenzene (1a): 2.24 mL; 22 mmol) and methylacrylate (906 μL; 10 mmol)
were added. The reaction mixture was purged with argon for 5 min. After addition of
norbornene (942 mg; 10 mmol) the tube was sealed and heated at 90 °C for 18 h.
®
For workup the cooled reaction mixture was filtered over Celite , washed with DCM,
concentrated in vacuo and purified by column chromatography.
Methyl (2E)-3-[2,6-bis(3-bromopropyl)phenyl]prop-2-enoate (2a)
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
Yield: 544 mg (67%); yellow oil.
1
H NMR (250 MHz, CDCl ): 7.87 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 7.21 (m, 1H, aryl-H), 7.12
3
(
3
m, 2H, aryl-H), 6.03 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 3.83 (s, 3H, COOCH ), 3.38 (t,
J = 6.5 Hz, 4H, CH -Br), 2.79 (t, J = 7.3 Hz, 4H, CH -CH -CH -Br), 2.07 (m, 4H, CH -CH -Br).
2
2
2
2
2
2
13
3
C NMR (63 MHz, CDCl ): 166.5, 143.2, 139.0, 134.2, 128.4, 127.7, 124.8, 51.8, 33.6, 33.0,
3
2.0. IR (neat): 2949 (m), 1722 (s), 1641 (m), 1576 (w), 1456 (m), 1434 (m), 1309 (m), 1272
(
3
m), 1195 (m), 1169 (s), 1038 (w), 984 (m), 866 (w), 793 (w), 764 (m). R (n-hexane/EtOAc,
f
+
:1) = 0.70. HRMS: calcd for C16
H21Br
O
2 2
[M+H] 402.9903: found 402.9900.
Methyl (2E)-3-[2-(3-bromopropyl)-6-methylphenyl]prop-2-enoate (2b)
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
Yield: 567 mg (95%); orange oil.
1
H NMR (250 MHz, CDCl
3
): 7.86 (d, J = 16.5 Hz, 1H, aryl-CH=CH), 7.21 – 7.08 (m, 3H, aryl-
), 3.39 (t, J = 6.5 Hz, 2H,
CH -Br), 2.82 (t, J = 7.5 Hz, 2H, CH -CH -CH -Br), 2.33 (s, 3H, CH ), 2.08 (m, 2H, CH -CH -
H), 6.06 (d, J = 16.5 Hz, 1H, aryl-CH=CH), 3.83 (s, 3H, COOCH
3
2
2
2
2
3
2
2
13
Br). C NMR (63 MHz, CDCl
3
): 166.8, 143.3, 139.1, 136.5, 134.0, 128.7, 128.4, 127.3,
24.2, 51.7, 33.6, 33.0, 32.0, 21.1. IR (neat): 2950 (s), 1721 (s), 1639 (s), 1525 (w), 1436 (s),
308 (s), 1267 (s), 1168 (s), 1038 (m), 987 (m), 865 (w), 766 (m). R (n-hexane/EtOAc, 3:1) =
.75. HRMS: calcd for C H BrO [M+H] 297.0485: found 297.0486.
1
1
0
f
+
14
18
2
Methyl (2E)-3-[2-(3-bromopropyl)-6-methoxyphenyl]prop-2-enoate (2c)
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
Yield: 430 mg (69%); colourless oil.
1
H NMR (250 MHz, CDCl ): 7.86 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 7.24 (m, 1H, aryl-H),
3
6
.89 – 6.81 (m, 2H, aryl-H), 6.72 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 3.87 (s, 3H, COOCH ),
3
5
ꢀ
ꢀ

3
.81 (s, 3H, OCH ), 3.40 (t, J = 6.5 Hz, 2H, CH -Br), 2.93 (t, J = 7.3 Hz, 2H, CH -CH -CH -
3 2 2 2 2
13
Br), 2.12 (m, 2H, CH -CH -Br). C NMR (63 MHz, CDCl ): 168.3, 159.4, 142.3, 138.2, 130.2,
2
2
3
1
(
1
22.6, 122.5, 121.9, 109.3, 55.5, 51.6, 33.9, 32.9, 32.1. IR (neat): 2948 (m), 2839 (w), 1714
s), 1627 (s), 1595 (s), 1573 (m), 1470 (s), 1436 (s), 1312 (s), 1266 (s), 1193 (s), 1167 (s),
075 (s), 986 (m), 948 (w), 869 (w), 791 (m), 756 (m). R (n-hexane/EtOAc, 3:1) = 0.60.
HRMS: calcd for C H BrO [M+H] 313.0434: found 313.0434.
f
+
14
18
3
Methyl (2E)-3-[2-(3-bromopropyl)-6-(trifluoromethyl)phenyl]prop-2-enoate (2d)
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
Yield: 310 mg (44%); colourless oil.
1
3
H NMR (250 MHz, CDCl ): 7.88 (dd, J = 1.8 Hz, 16.3 Hz, 1H, aryl-CH=CH), 7.58 (d,
J = 8 Hz, 1H, aryl-H), 7.47 – 7.35 (m, 2H, aryl-H), 6.05 (d, J = 16.3 Hz, 1H, aryl-CH=CH),
3
CH
.83 (s, 3H, COOCH ), 3.38 (t, J = 6.5 Hz, 2H, CH -Br), 2.84 (t, J = 7.3 Hz, 2H, CH -CH -
3
2
2
2
13
2
2 2 3
-Br), 2.08 (m, 2H, CH -CH -Br). C NMR (63 MHz, CDCl ): 166.0, 140.6, 140.2, 132.96,
19
1
32.95, 128.2, 126.3, 126.2, 124.3, 124.2, 51.9, 33.3, 32.6, 31.6. F NMR (282 MHz,
CDCl ): - 58.2. IR (neat): 2953 (m), 1726 (s), 1652 (m), 1600 (w), 1458 (m), 1437 (m), 1320
s), 1280 (s), 1163 (s), 1125 (s), 1038 (m), 1010 (m), 981 (m), 865 (w), 804 (m), 764 (m), 719
3
(
(
+
w). R
f 3 2
(n-hexane/EtOAc, 3:1) = 0.65. HRMS: calcd for C14H15BrF O [M+H] 351.0202: found
3
51.0201.
Methyl (2E)-3-[2-(3-bromopropyl)-6-phenylphenyl]prop-2-enoate (2e)
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
Yield: 379 mg (53%); yellow oil.
1
H NMR (250 MHz, CDCl
3
): 7.76 (d, J = 16.5 Hz, 1H, aryl-CH=CH), 7.37 – 7.19 (m, 8H, aryl-
), 3.43 (t, J = 6.5 Hz, 2H,
H), 5.66 (d, J = 16.5 Hz, 1H, aryl-CH=CH), 3.69 (s, 3H, COOCH
CH -Br), 2.93 (t, J = 7.5 Hz, 2H, CH -CH -CH -Br), 2.12 (m, 2H, CH -CH -Br). C NMR (63
3
13
2
2
2
2
2
2
3
MHz, CDCl ): 166.7, 142.9, 142.4, 141.2, 139.7, 132.7, 129.7, 128.9, 128.5, 128.2, 127.2,
1
1
1
0
24.8, 51.6, 33.7, 33.0, 32.1. IR (neat): 3057 (m), 3023 (m), 2949 (m), 1719 (s), 1637 (m),
572 (w), 1496 (w), 1458 (m), 1436 (s), 1309 (s), 1270 (s), 1234 (m), 1195 (s), 1170 (s),
073 (w), 1037 (m), 983 (m), 865 (w), 801 (m), 763 (s), 702 (s). R (n-hexane/EtOAc, 3:1) =
[M+H] 359.0641: found 359.0642.
f
+
.70. HRMS: calcd for C19H20BrO
2
Methyl (2E)-3-[2-(3-bromopropyl)naphthalen-1-yl]prop-2-enoate (2f)
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
Yield: 597 mg (90%); yellow oil.
1
H NMR (250 MHz, CDCl
.85 – 7.77 (m, 2H, aryl-H), 7.53 – 7.43 (m, 2H, aryl-H), 7.38 (d, J = 8.5 Hz, 1H, aryl-H), 6.23
d, J = 16.3 Hz, 1H, aryl-CH=CH), 3.88 (s, 3H, COOCH ), 3.42 (t, J = 6.5 Hz, 2H, CH -Br),
3
): 8.20 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 8.03 (m, 1H, aryl-H),
7
(
3
2
6
ꢀ
ꢀ

13
2
.99 (t, J = 7.8 Hz, 2H, CH -CH -CH -Br), 2.18 (m, 2H, CH -CH -Br). C NMR (63 MHz,
2 2 2 2 2
CDCl ): 166.7, 142.5, 136.4, 132.3, 131.3, 131.1, 128.9, 128.2, 127.5, 126.6, 125.8, 125.5,
3
1
1
24.9, 51.8, 33.8, 32.9, 32.1. IR (neat): 3052 (m), 2950 (m), 1721 (s), 1641 (m), 1508 (w),
435 (m), 1272 (s), 1171 (s), 1037 (m), 986 (m), 865 (w), 818 (m), 751 (m). R (n-
Na [M+Na] 355.0304: found
f
+
hexane/EtOAc, 3:1) = 0.65. HRMS: calcd for C17
H17BrO
2
3
55.0307.
Methyl (2E)-3-[2-(3-bromopropyl)anthracen-1-yl]prop-2-enoate (2g)
Eluent for column chromatography: n-hexane/EtOAc, 50:1 Æ 25:1.
Yield: 585 mg (76%); yellow solid after recrystallization from MeCN.
1
H NMR (250 MHz, CDCl
H, aryl-CH=CH), 8.02 – 7.93 (m, 3H, aryl-H), 7.51 – 7.45 (m, 2H, aryl-H), 7.35 (d,
J = 8.8 Hz, 1H, aryl-H), 6.35 (d, J = 16.5 Hz, 1H, aryl-CH=CH), 3.92 (s, 3H, COOCH ), 3.45
3
): 8.54 (s, 1H, aryl-H), 8.40 (s, 1H, aryl-H), 8.32 (d, J = 16.3 Hz,
1
3
(
t, J = 6.5 Hz, 2H, CH
2
-Br), 3.03 (t, J = 7.3 Hz, 2H, CH
2 2 2 2 2
-CH -CH -Br), 2.22 (m, 2H, CH -CH -
13
Br). C NMR (63 MHz, CDCl ): 166.9, 142.6, 136.0, 132.1, 131.3, 130.7, 130.5, 129.7,
3
1
29.3, 128.5, 127.8, 127.4, 126.7, 125.76, 125.75, 125.7, 123.8, 51.9, 33.9, 32.9, 32.3. IR
(
(
(
neat): 2945 (w), 1710 (s), 1634 (w), 1455 (w), 1437 (m), 1321 (w), 1264 (s), 1193 (m), 1166
m), 1133 (w), 1038 (s), 981 (m), 877 (s), 858 (m), 803 (w), 739 (s), 715 (m), 653 (w), 619
f 2
w), 554 (m). mp: 74 - 77 °C. R (n-hexane/EtOAc, 3:1) = 0.55. HRMS: calcd for C21H19BrO
+
[M] 382.0563: found 382.0561.
Methyl (2E)-3-[10-(3-bromopropyl)phenanthren-9-yl]prop-2-enoate (2h)
Eluent for column chromatography: n-hexane/EtOAc 25:1, Æ 10:1.
Yield: 219 mg (29%); colourless solid after recrystallization from DCM/n-hexane.
1
3
H NMR (250 MHz, CDCl ): 8.76 – 8.69 (m, 2H, aryl-H), 8.26 (d, J = 16.3 Hz, 1H, aryl-
CH=CH), 8.17 (m, 1H, aryl-H), 8.00 (m, 1H, aryl-H), 7.70 – 7.55 (m, 4H, aryl-H), 6.23 (d,
J = 16.3 Hz, 1H, aryl-CH=CH), 3.90 (s, 3H, COOCH ), 3.55 (t, J = 6.5 Hz, 2H, CH -Br), 3.34
t, J = 8 Hz, 2H, CH -CH -CH -Br), 2.23 (m, 2H, CH -CH -Br). C NMR (63 MHz, CDCl3):
3
2
13
(
2
2
2
2
2
1
1
66.6, 144.0, 133.1, 130.7, 130.6, 130.3, 130.0, 129.7, 127.2, 126.9, 126.5, 126.3, 126.1,
24.8, 123.2, 122.8, 110.0, 51.9, 33.5, 33.2, 28.8 ppm. IR (KBr): 3072 (w), 2951 (w), 1717
(
7
3
s), 1639 (m), 1493 (w), 1432 (m), 1322 (m), 1270 (s), 1176 (s), 1035 (w), 1006 (w), 758 (s),
26 (m). mp: 93 – 96 °C. R (n-hexane/EtOAc, 3:1) = 0.65. HRMS: calcd for C21H19BrO [M]
f 2
82.0563: found 382.0569.
+
Methyl (2E)-3-[2-(3-bromopropyl)pyren-1-yl]prop-2-enoate (2i)
Eluent for column chromatography: n-hexane/EtOAc 25:1, Æ 10:1.
Yield: 562 mg (69%); yellow solid after recrystallization from MeCN.
7
ꢀ
ꢀ

1
3
H NMR (250 MHz, CDCl ): 8.43 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 8.33 (d, J = 9.5 Hz, 1H,
aryl-H), 8.18 (d, J = 7.5 Hz, 2H, aryl-H), 8.10 – 7.97 (m, 5H, aryl-H), 6.38 (d, J = 16.3 Hz, 1H,
aryl-CH=CH), 3.93 (s, 3H, COOCH ), 3.48 (t, J = 6.5 Hz, 2H, CH -Br), 3.25 (t, J = 7.3 Hz, 2H,
3
2
13
CH
2
-CH
2
-CH
2
2 2 3
-Br), 2.31 (m, 2H, CH -CH -Br). C NMR (63 MHz, CDCl ): 166.8, 142.8,
1
1
1
36.6, 131.4, 131.1, 130.5, 129.5, 129.2, 128.3, 128.2, 127.0, 126.3, 126.0, 125.8, 125.6,
25.3, 124.6, 124.4, 123.7, 51.9, 34.0, 33.0, 32.6. IR (KBr): 2927 (m), 2857 (w), 1721 (s),
638 (m), 1596 (w), 1437 (m), 1285 (s), 1200 (m), 1171 (s), 988 (m), 884 (m), 842 (s), 763
(
f
m), 713 (m), 671 (w), 604 (w). mp: 121 – 124 °C. R (n-hexane/EtOAc, 3:1) = 0.60.
Elementary analysis: calcd for C H BrO (407.30): C 67.82, H 4.70; found C 67.56,
23
19
2
H 4.76.
Methyl (2E)-3-[2-(3-bromopropyl)-1-[(4-methylbenzene)sulfonyl]-1H-indol-3-yl]prop-2-
enoate (2j)
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1 Æ 5:1.
1
Yield: 71 mg (7%) (calculated from the H NMR with mesitylene as standard); colourless
solid after recrystallization from DCM/n-hexane.
1
H NMR (250 MHz, CDCl
m, 1H, aryl-H), 7.62 (d, J = 8.3 Hz, 2H, aryl-H), 7.40 – 7.29 (m, 2H, aryl-H), 7.21 (d,
J = 8 Hz, 2H, aryl-H), 6.54 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 3.82 (s, 3H, COOCH ), 3.48 (t,
J = 6.5 Hz, 2H, CH -Br), 3.33 (t, J = 7.3 Hz, 2H, CH -CH -CH -Br), 2.35 (s, 3H, CH ), 2.32
m, 2H, CH -CH -Br). C NMR (63 MHz, CDCl ): 167.6, 145.4, 142.4, 137.0, 135.3, 130.1,
3
): 8.25 (m, 1H, aryl-H), 7.88 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 7.78
(
3
2
2
2
2
3
13
(
2
2
3
1
27.4, 126.3, 125.2, 124.5, 120.1, 118.9, 117.1, 115.3, 105.0, 51.7, 33.7, 32.7, 25.4, 21.6. IR
(
(
(
KBr): 2951 (m), 2371 (w), 1715 (s), 1632 (s), 1447 (m), 1372 (s), 1279 (s), 1232 (m), 1175
s), 1121 (m), 1088 (m), 1008 (m), 978 (m), 850 (w), 812 (w), 746 (m), 681 (m), 657 (w), 574
s). mp: 104 – 106 °C. R
f
(n-hexane/EtOAc, 3:1) = 0.55. MS (ESI): calcd for C22
H
22BrNO
4
S
+
+
+
+
[M] 475.05, found 396.5 (100.00) [M-Br] , 476.4 (42.95) [M+H] , 498.4 (75.62) [M+Na] .
General procedure for the substitution reaction with HNBoc (3a-i); GP3:
2
The alkyl bromide 2a-i (1 equiv), Cs
2 3 2
CO (2 equiv; for 2a 3 equiv) and HNBoc (1.1 equiv; for
2
a 2.1 equiv) were dissolved in dry DMF in a sealable tube and heated to 90 °C overnight.
For workup H O was added and the reaction mixture was extracted with EtOAc (3x). The
2
combined organic layers were dried over MgSO , concentrated in vacuo and purified by
4
column chromatography.
Methyl (2E)-3-[2,6-bis(3-{bis[(tert-butoxy)carbonyl]amino}propyl)phenyl]prop-2-enoate
(
3a)
Following GP3 using bromide 2a (904 mg; 2.24 mmol), Cs CO (2.19 g; 6.72 mmol) and
2 3
HNBoc (1.02 g; 4.70 mmol) in dry DMF (10 mL).
2
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
8
ꢀ
ꢀ

Yield: 1.51 g (99%); colourless oil.
1
H NMR (250 MHz, CDCl
3
): 7.84 (d, J = 16.5 Hz, 1H, aryl-CH=CH), 7.23 – 7.06 (m, 3H, aryl-
), 3.58 (t, J = 7.5 Hz, 4H,
), 1.81 (m, 4H, CH -CH -NBoc ),
H), 6.00 (d, J = 16.5 Hz, 1H, aryl-CH=CH), 3.80 (s, 3H, COOCH
CH -NBoc ), 2.61 (t, J = 7.8 Hz, 4H, CH -CH -CH -NBoc
1
1
3
2
2
2
2
2
2
2
2
2
13
.48 (s, 36H, t-Bu). C NMR (63 MHz, CDCl ): 166.4, 152.5, 143.4, 139.8, 133.9, 128.3,
3
26.9, 124.5, 82.1, 51.6, 46.2, 30.9, 30.1, 28.1. IR (neat): 2979 (s), 1789 (m), 1726 (s), 1696
(
9
s), 1642 (w), 1456 (m), 1393 (s), 1367 (s), 1303 (s), 1170 (s), 1138 (s), 1113 (s), 1041 (w),
83 (w), 888 (w), 855 (m), 763 (m). R (n-hexane/EtOAc, 3:1) = 0.50. HRMS: calcd for
C H N O Na [M+Na] 699.3827: found 699.3821.
f
+
36
56
2
10
Methyl
(2E)-3-[2-(3-{bis[(tert-butoxy)carbonyl]amino}propyl)-6-methylphenyl]prop-2-
enoate (3b)
2 3
Following GP3 using bromide 2b (300 mg; 1.01 mmol), Cs CO (658 mg; 2.02 mmol) and
HNBoc (241 mg; 1.11 mmol) in dry DMF (5 mL).
2
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
Yield: 421 mg (96%); colourless oil.
1
3
H NMR (250 MHz, CDCl ): 7.84 (d, J = 16.5 Hz, 1H, aryl-CH=CH), 7.16 (m, 1H, aryl-H),
7
3
3
1
3
.13 – 7.05 (m, 2H, aryl-H), 6.04 (d, J = 16.5 Hz, 1H, aryl-CH=CH), 3.81 (s, 3H, COOCH ),
3
.59 (t, J = 7.5 Hz, 2H, CH -NBoc ), 2.64 (t, J = 7.8 Hz, 2H, CH -CH -CH -NBoc ), 2.32 (s,
2
2
2
2
2
2
13
H, CH
3
), 1.83 (m, 2H, CH
2
-CH
2
2 3
-NBoc ), 1.48 (s, 18H, t-Bu). C NMR (63 MHz, CDCl ):
66.8, 152.5, 143.5, 140.0, 136.3, 133.9, 128.4, 128.3, 126.8, 124.1, 82.1, 51.6, 46.2, 30.9,
0.1, 28.0, 21.1. IR (neat): 2979 (m), 1789 (w), 1724 (s), 1697 (s), 1640 (w), 1525 (w), 1458
(
9
[
m), 1438 (m), 1393 (m), 1367 (s), 1306 (s), 1270 (m), 1170 (s), 1137 (s), 1111 (s), 1039 (w),
86 (w), 856 (m), 763 (m). R (n-hexane/EtOAc, 3:1) = 0.65. HRMS: calcd for C24 Na
M+Na] 456.2357: found 456.2370.
f
H35NO
6
+
Methyl (2E)-3-[2-(3-{bis[(tert-butoxy)carbonyl]amino}propyl)-6-methoxyphenyl]prop-2-
enoate (3c)
Following GP3 using bromide 2c (566 mg; 1.81 mmol), Cs
HNBoc (432 mg; 1.99 mmol) in dry DMF (12 mL).
2 3
CO (1.18 g; 3.62 mmol) and
2
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
Yield: 697 mg (86%); colourless oil.
1
H NMR (250 MHz, CDCl
3
): 7.85 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 7.21 (m, 1H, aryl-H), 6.81
(
m, 2H, aryl-H), 6.67 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 3.85 (s, 3H, COOCH ), 3.79 (s, 3H,
3
OCH
1
1
3
), 3.60 (t, J = 7.5 Hz, 2H, CH
.85 (m, 2H, CH -CH -NBoc ), 1.46 (s, 18H, t-Bu). C NMR (63 MHz, CDCl
52.4, 143.2, 138.3, 130.1, 122.5, 122.1, 109.0, 82.1, 81.9, 55.4, 51.5, 46.1, 31.0, 30.3, 28.0.
2
-NBoc
2
), 2.75 (t, J = 7.8 Hz, 2H, CH
2
-CH
2 2 2
-CH -NBoc ),
13
): 168.1, 159.2,
3
2
2
2
IR (neat): 2979 (m), 1791 (m), 1716 (s), 1628 (m), 1595 (m), 1574 (m), 1471 (m), 1393 (m),
1
367 (s), 1310 (m), 1264 (s), 1168 (s), 1137 (s), 1112 (s), 1041 (w), 986 (w), 853 (m), 784
9
ꢀ
ꢀ

+
(
m), 757 (m). R (n-hexane/EtOAc, 3:1) = 0.50. HRMS: calcd for C H NO K [M+K]
f
24 35
7
4
88.2045: found 488.2032.
Methyl (2E)-3-[2-(3-{bis[(tert-butoxy)carbonyl]amino}propyl)-6-(trifluoromethyl)phenyl]
prop-2-enoate (3d)
Following GP3 using bromide 2d (285 mg; 0.81 mmol), Cs CO (528 mg; 1.62 mmol) and
2
3
HNBoc (193 mg; 0.89 mmol) in dry DMF (6 mL).
2
Eluent for column chromatography: n-hexane/EtOAc, 10:1.
Yield: 359 mg (91%); colourless oil.
1
3
H NMR (250 MHz, CDCl ): 7.87 (dd, J = 1.5 Hz, 16.3 Hz, 1H, aryl-CH=CH), 7.55 (d, J = 7.3
Hz, 1H, aryl-H), 7.44 – 7.33 (m, 2H, aryl-H), 6.03 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 3.82 (s,
H, COOCH ), 3.59 (t, J = 7.3 Hz, 2H, CH -NBoc ), 2.65 (t, J = 7.8 Hz, 2H, CH -CH -CH
NBoc ), 1.83 (m, 2H, CH -CH -NBoc ), 1.48 (s, 18H, t-Bu). C NMR (63 MHz, CDCl ): 166.0,
3
3
2
2
2
2
2
-
13
2
2
2
2
3
1
3
1
52.5, 141.1, 140.8, 133.7, 132.5, 128.1, 126.10, 126.07, 123.94, 123.85, 82.3, 51.8, 46.0,
19
0.5, 29.8, 28.0. F NMR (282 MHz, CDCl
3
): - 58.1. IR (neat): 2980 (m), 1795 (m), 1730 (s),
654 (s), 1458 (m), 1394 (m), 1368 (s), 1319 (s), 1139 (s), 1041 (w), 981 (w), 853 (m), 806
+
(
w), 764 (w). R
f
32 3 6
(n-hexane/EtOAc, 3:1) = 0.60. HRMS: calcd for C24H F NO Na [M+Na]
5
10.2074: found 510.2066.
Methyl
(2E)-3-[2-(3-{bis[(tert-butoxy)carbonyl]amino}propyl)-6-phenylphenyl]prop-2-
enoate (3e)
Following GP3 using bromide 2e (367 mg; 1.02 mmol), Cs CO (665 mg; 2.04 mmol) and
2
3
2
HNBoc (243 mg; 1.12 mmol) in dry DMF (7 mL).
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
Yield: 454 mg (90%); colourless oil.
1
3
H NMR (250 MHz, CDCl ): 7.73 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 7.39 – 7.29 (m, 5H, aryl-
H), 7.23 – 7.16 (m, 3H, aryl-H), 5.67 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 3.69 (s, 3H,
COOCH ), 3.63 (t, J = 7.5 Hz, 2H, CH -NBoc ), 2.75 (t, J = 8 Hz, 2H, CH -CH -CH -NBoc ),
.89 (m, 2H, CH -CH -NBoc ), 1.48 (s, 18H, t-Bu). C NMR (63 MHz, CDCl ): 166.6, 152.5,
3
2
2
2
2
2
2
1
3
1
1
5
1
2
2
2
3
43.1, 142.3, 141.3, 140.6, 132.6, 129.7, 128.6, 128.49, 128.46, 128.1, 127.1, 124.6, 82.1,
1.5, 46.2, 31.1, 30.2, 28.1. IR (neat): 2979 (m), 1790 (m), 1723 (s), 1638 (m), 1458 (m),
438 (m), 1393 (m), 1367 (s), 1306 (m), 1170 (s), 1138 (s), 1114 (s), 1040 (w), 983 (w), 854
(
w), 763 (m), 702 (m). R
f
(n-hexane/EtOAc, 3:1) = 0.55. HRMS: calcd for C29
6
H37NO Na
+
[
M+Na] 518.2513: found 518.2506.
1
0ꢀ
ꢀ

Methyl
(2E)-3-[2-(3-{bis[(tert-butoxy)carbonyl]amino}propyl)naphthalen-1-yl]prop-2-
enoate (3f)
Following GP3 using bromide 2f (582 mg; 1.75 mmol), Cs CO (1.14 g; 3.50 mmol) and
2
3
2
HNBoc (419 mg; 1.93 mmol) in dry DMF (8 mL).
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
Yield: 747 mg (91%); light yellow oil.
1
H NMR (250 MHz, CDCl
.83 – 7.76 (m, 2H, aryl-H), 7.51 – 7.42 (m, 2H, aryl-H), 7.36 (d, J = 8.5 Hz, 1H, aryl-H), 6.22
d, J = 16.3 Hz, 1H, aryl-CH=CH), 3.87 (s, 3H, COOCH ), 3.64 (t, J = 7.5 Hz, 2H, CH
), 1.91 (m, 2H, CH -CH -NBoc ), 1.47 (s,
): 166.7, 152.5, 142.6, 137.5, 132.2, 131.4, 130.7,
3
): 8.18 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 8.01 (m, 1H, aryl-H),
7
(
3
2
-
NBoc
2
), 2.82 (t, J = 7.8 Hz, 2H, CH
2
2 2
-CH -CH -NBoc
2
2
2
2
13
1
1
2
1
8H, t-Bu). C NMR (63 MHz, CDCl
3
28.8, 128.2, 127.4, 126.5, 125.7, 125.4, 124.9, 82.1, 51.7, 46.2, 31.2, 30.4, 28.0. IR (neat):
979 (s), 1791 (m), 1725 (s), 1642 (m), 1595 (w), 1509 (m), 1479 (m), 1436 (m), 1368 (s),
299 (s), 1171 (s), 1134 (s), 1042 (m), 986 (m), 856 (m), 819 (m), 754 (m). R
f
(n-
+
hexane/EtOAc, 3:1) = 0.60. HRMS: calcd for C27
92.2373.
H35NO Na [M+Na] 492.2357: found
6
4
Methyl
(2E)-3-[2-(3-{bis[(tert-butoxy)carbonyl]amino}propyl)anthracen-1-yl]prop-2-
enoate (3g)
2 3
Following GP3 using bromide 2g (627 mg; 1.64 mmol), Cs CO (1.07 g; 3.28 mmol) and
HNBoc (391 mg; 1.80 mmol) in dry DMF (11 mL).
2
Eluent for column chromatography: n-hexane/EtOAc, 50:1 Æ 25:1 Æ 10:1.
Yield: 652 mg (77%); yellow solid after recrystallization from MeCN.
1
H NMR (250 MHz, CDCl
H, aryl-CH=CH), 8.02 – 7.92 (m, 3H, aryl-H), 7.50 – 7.44 (m, 2H, aryl-H), 7.34 (d,
J = 8.8 Hz, 1H, aryl-H), 6.33 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 3.91 (s, 3H, COOCH ), 3.66
t, J = 7.5 Hz, 2H, CH -NBoc ), 2.86 (t, J = 8 Hz, 2H, CH -CH -CH -NBoc ), 1.95 (m, 2H,
CH -CH -NBoc ), 1.48 (s, 18H, t-Bu). C NMR (63 MHz, CDCl ): 166.8, 152.5, 142.8, 137.0,
3
): 8.52 (s, 1H, aryl-H), 8.39 (s, 1H, aryl-H), 8.30 (d, J = 16.5 Hz,
1
3
(
2
2
2
2
2
2
13
2
2
2
3
1
1
1
32.0 131.2, 130.5, 130.2, 129.8, 129.2, 128.5, 127.8, 127.3, 126.6, 125.7, 125.61, 125.59,
23.7, 82.2, 51.8, 46.3, 31.3, 30.4, 28.1. IR (neat): 2987 (w), 1747 (m), 1712 (s), 1641 (w),
462 (w), 1368 (m), 1292 (m), 1273 (m), 1164 (s), 1126 (s), 1106 (s), 983 (m), 885 (m), 861
(
0
m), 806 (w), 780 (m), 745 (s), 714 (w), 622 (w). mp: 91 – 94 °C. R
f
(n-hexane/EtOAc, 3:1) =
.65. HRMS: calcd for C31H37NO Na [M+Na] 542.2513: found 542.2506.
6
+
Methyl (2E)-3-[10-(3-{bis[(tert-butoxy)carbonyl]amino}propyl)phenanthren-9-yl]prop-2-
enoate (3h)
Following GP3 using bromide 2h (411 mg; 1.07 mmol), Cs CO (697 mg; 2.14 mmol) and
2
3
2
HNBoc (256 mg; 1.18 mmol) in dry DMF (8 mL).
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
1ꢀ
1
ꢀ

Yield: 448 mg (81%); colourless solid after recrystallization from DCM/n-hexane.
1
H NMR (250 MHz, CDCl
m, 1H, aryl-H), 7.99 (dd, J = 1 Hz, 7.8 Hz, 1H, aryl-H), 7.70 – 7.54 (m, 4H, aryl-H), 6.22 (d,
J = 16.5 Hz, 1H, aryl-CH=CH), 3.89 (s, 3H, COOCH ), 3.75 (t, J = 7.3 Hz, 2H, CH -NBoc ),
3
): 8.72 (m, 2H, aryl-H), 8.24 (d, J = 16.5 Hz, 1H, aryl-CH=CH), 8.11
(
3
2
2
3
.16 (t, J = 8.3 Hz, 2H, CH -CH -CH -NBoc ), 1.96 (m, 2H, CH -CH -NBoc ), 1.49 (s, 18H, t-
2
2
2
2
2
2
2
13
Bu). C NMR (63 MHz, CDCl
3
): 166.5, 152.5, 144.0, 133.9, 130.6, 130.3, 130.2, 130.1,
1
3
29.6, 127.0, 126.79, 126.76, 126.3, 126.2, 126.0, 124.9, 123.2, 122.7, 82.2, 51.8, 46.4,
0.0, 28.0, 27.5. IR (neat): 2977 (s), 1785 (m), 1725 (s), 1643 (m), 1525 (w), 1440 (m), 1364
(
s), 1267 (s), 1170 (s), 1138 (s), 1042 (m), 988 (w), 856 (m), 755 (s). mp: 81 – 84 °C. R
f
(n-
+
hexane/EtOAc, 3:1) = 0.55. HRMS: calcd for C31
6
H37NO Na [M+Na] 542.2513: found
5
42.2505.
Methyl (2E)-3-[2-(3-{bis[(tert-butoxy)carbonyl]amino}propyl)pyren-1-yl] prop-2-enoate
3i)
(
2 3
Following GP3 using bromide 2i (418 mg; 1.03 mmol), Cs CO (671 mg; 2.06 mmol) and
HNBoc (246 mg; 1.13 mmol) in dry DMF (8 mL).
2
Eluent for column chromatography: n-hexane/EtOAc, 25:1 Æ 10:1.
Yield: 553 mg (99%); yellow solid after recrystallization from DCM/n-hexane.
1
3
H NMR (250 MHz, CDCl ): 8.42 (d, J = 16.3 Hz, 1H, aryl-CH=CH), 8.33 (d, J = 9.3 Hz, 1H,
aryl-H), 8.18 (d, J = 7.8 Hz, 2H, aryl-H), 8.10 – 7.96 (m, 5H, aryl-H), 6.37 (d, J = 16.3 Hz, 1H,
aryl-CH=CH), 3.91 (s, 3H, COOCH ), 3.72 (t, J = 7.5 Hz, 2H, CH -NBoc ), 3.09 (t, J = 8 Hz,
H, CH -CH -CH -NBoc ), 2.07 (m, 2H, CH -CH -NBoc ), 1.47 (s, 18H, t-Bu). C NMR
63 MHz, CDCl ): 166.7, 152.6, 142.9, 137.6, 131.3, 131.0, 130.4, 129.4, 129.0, 128.1,
3
2
2
13
2
2
2
2
2
2
2
2
(
3
1
3
28.0, 127.0, 126.1, 125.9, 125.4, 125.2, 124.5, 124.431, 124.426, 123.5, 82.1, 51.8, 46.3,
1.6, 30.5, 28.0. IR (KBr): 2978 (m), 2869 (w), 1749 (s), 1712 (s), 1629 (w), 1598 (w), 1443
(
(
m), 1364 (s), 1306 (s), 1264 (s), 1136 (s), 1033 (m), 987 (w), 887 (w), 855 (m), 777 (m), 717
w), 688 (w). mp: 130 – 132 °C. R (n-hexane/EtOAc, 3:1) = 0.50. HRMS: calcd for
f
+
C H NO [M] 543.2615: found 543.2619.
33
37
6
General procedure for the conversion to the carboximides (5a-i); GP4:
The starting material was dissolved in MeOH (or in some cases in a mixture of MeOH and
EtOAc). After addition of palladium on activated carbon (10% Pd basis, moistened with
water; 20 wt-%) the reaction mixture was stirred under a H atmosphere for 8 h. The catalyst
2
®
was removed by filtration over Celite and the solvent was removed under reduced pressure.
The crude product was dissolved in MeOH and an aq NaOH solution (8 M; 1:1, v/v) was
added. The reaction mixture was stirred at room temperature overnight.
For workup the solution was acidified with HCl (4 M) under ice cooling and extracted with
DCM (3x). After drying over MgSO the solvent was removed under reduced pressure.
4
1
2ꢀ
ꢀ

The crude carboxylic acid was dissolved in dry THF under an argon atmosphere and cooled
to -78 °C. Pivaloylchloride (1.2 equiv) and NEt (1.5 equiv) were added which led to the
3
formation of a colourless precipitate. The mixture was stirred at -78 °C for 15 min and at 0 °C
for 45 min.
In a second flask (R)-4-benzyl-2-oxazolidinone (2 equiv) was dissolved in THF under an
argon atmosphere and cooled to -78 °C. After dropwise addition of n-butyllithium (1.6 M in
hexane; 1.9 equiv), it was stirred at -78 °C for approximately 30 min.
After 45 min at 0 °C the activated carboxylic acid was again cooled to -78 °C and the lithiated
oxazolidinone was added. The reaction mixture was then allowed to warm to room
temperature overnight.
For workup diluted NaHCO
combined organic phases were washed with diluted NaHCO
3
solution was added and it was extracted with DCM (3x). The
-solution and with brine, dried
3
over MgSO and concentrated under reduced pressure. The product was purified by column
4
chromatography.
tert-Butyl N-[3-(2-{3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl}-3-(3-{[(tert-
butoxy)carbonyl]amino}propyl)phenyl)propyl] carbamate (5a)
Following GP4 using methylester 3a (2.07 g; 3.06 mmol), Pd/C (414 mg), MeOH (30 mL);
NaOH (8 M; 20 mL), MeOH (20 mL); Piv-Cl (452 μL; 3.67 mmol), NEt (640 μL; 4.59 mmol),
3
dry THF (34 mL), (R)-4-benzyl-2-oxazolidinone (1.08 g; 6.12 mmol), n-BuLi (1.6 M in n-
hexane; 3.63 mL; 5.81 mmol), dry THF (17 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 3:1 Æ 1:1.
Yield: 1.38 g (72% over 3 steps); colourless solid after recrystallization from DCM/n-hexane.
1
H NMR (250 MHz, CDCl
3
): 7.39 – 7.29 (m, 3H, aryl-H), 7.25 – 7.22 (m, 2H, aryl-H), 7.14 –
7
.01 (m, 3H, aryl-H), 4.76 – 4.61 (m, 3H, CH + NH), 4.29 – 4.17 (m, 2H, CH -O), 3.37 (dd,
2
2
J = 3.3 Hz, 13.3 Hz, 1H, CHH-phenyl), 3.21 (m, 4H, CH -NH-Boc), 3.13 – 2.97 (m, 4H, CH
2
-
CO + CH
2
-CH
2
-CO), 2.81 (dd, J = 9.8 Hz, 13.3 Hz, 1H, CHH-phenyl), 2.69 (t, J = 7.8 Hz, 4H,
13
CH -CH -CH
2
2
2 2 2
-NH-Boc), 1.79 (m, 4H, CH -CH -NH-Boc), 1.44 (s, 18H, t-Bu). C NMR
(
63 MHz, CDCl ): 172.4, 156.0, 153.5, 140.3, 135.9, 135.3, 129.4, 129.0, 127.5, 127.4,
3
1
26.6, 79.1, 66.4, 55.3, 40.8, 38.0, 36.4, 31.9, 30.3, 28.4, 23.6. IR (neat): 3370 (m), 2972
(
(
(
m), 1788 (s), 1702 (m), 1683 (s), 1519 (s), 1445 (w), 1395 (m), 1366 (s), 1294 (m), 1249
m), 1216 (s), 1166 (s), 1119 (m), 1058 (m), 870 (w), 782 (w), 757 (w), 733 (w), 699 (m), 599
20
m). mp: 126 – 128 °C. R
f
(n-hexane/EtOAc, 2:1) = 0.25. [D]
D
= -55.5° (c = 0.94, MeOH).
+
HRMS: calcd for C H N O K [M+K] 662.3202: found 662.3198.
35
49
3
7
tert-Butyl
N-[3-(2-{3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl}-3-methyl
phenyl)propyl]carbamate (5b)
Following GP4 using methylester 3b (362 mg; 0.83 mmol), Pd/C (72 mg), MeOH (8 mL);
NaOH (8 M; 5 mL), MeOH (5 mL); Piv-Cl (123 μL; 1.00 mmol), NEt (174 μL; 1.25 mmol), dry
3
1
3ꢀ
ꢀ

THF (9 mL), (R)-4-benzyl-2-oxazolidinone (294 mg; 1.66 mmol), n-BuLi (1.6 M in n-hexane;
88 μL; 1.58 mmol), dry THF (4.5 mL).
9
Eluent for column chromatography: cyclohexane/EtOAc, 3:1 Æ 1:1.
Yield: 321 mg (80% over 3 steps); colourless solid after recrystallization from DCM/n-hexane.
1
H NMR (250 MHz, CDCl
3
): 7.39 – 7.29 (m, 3H, aryl-H), 7.25 – 7.22 (m, 2H, aryl-H), 7.11 –
7
.00 (m, 3H, aryl-H), 4.76 – 4.64 (m, 2H, CH + NH), 4.28 – 4.16 (m, 2H, CH -O), 3.36 (dd,
2
J = 3.3 Hz, 13.5 Hz, 1H, CHH-phenyl), 3.21 (t, J = 7 Hz, 2H, CH -NH-Boc), 3.14 – 2.98 (m,
2
2 2 2
4H, CH -CO + CH -CH -CO), 2.82 (dd, J = 9.5 Hz, 13.5 Hz, 1H, CHH-phenyl), 2.69 (t,
J = 7.8 Hz, 2H, CH -CH -CH -NH-Boc), 2.37 (s, 3H, CH ), 1.79 (m, 2H, CH -CH -NH-Boc),
2
2
2
3
2
2
1
3
1
1
2
3
.45 (s, 9H, t-Bu). C NMR (63 MHz, CDCl ): 172.6, 156.0, 153.4, 139.9, 136.7, 136.4,
35.3, 129.4, 129.0, 128.5, 127.4, 127.2, 126.4, 79.1, 66.3, 55.2, 40.7, 38.0, 35.4, 31.9, 30.2,
8.4, 24.0, 19.9. IR (neat): 3374 (w), 2981 (m), 1788 (s), 1760 (m), 1706 (s), 1680 (s), 1513
(
(
(
(
s), 1394 (m), 1365 (m), 1299 (m), 1274 (m), 1229 (m), 1209 (m), 1186 (s), 1164 (s), 1120
m), 1098 (m), 1049 (m), 991 (m), 978 (m), 866 (w), 780 (m), 761 (s), 735 (s), 701 (s), 676
20
m), 593 (m), 511 (w). mp: 55 – 57 °C. R
c = 1.09, MeOH). HRMS: calcd for C H N O K [M+K] 519.2256: found 519.2245.
f
(n-hexane/EtOAc, 2:1) = 0.40. [D]
D
= -63.2°
+
28
36
2
5
tert-Butyl N-[3-(2-{3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl}-3-methoxy
phenyl)propyl]carbamate (5c)
Following GP4 using methylester 3c (1.11 g; 2.47 mmol), Pd/C (222 mg), MeOH/EtOAc (3:1;
29 mL); NaOH (8 M; 17 mL), MeOH (17 mL); Piv-Cl (365 μL; 2.96 mmol), NEt
3
(517 μL;
3
.71 mmol), dry THF (29 mL), (R)-4-benzyl-2-oxazolidinone (875 mg; 4.94 mmol), n-BuLi
(
1.6 M in n-hexane; 2.93 mL; 4.69 mmol), dry THF (14.5 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 3:1 Æ 1:1.
Yield: 948 mg (77% over 3 steps); colourless solid after recrystallization from DCM/n-hexane.
1
3
H NMR (250 MHz, CDCl ): 7.38 – 7.28 (m, 3H, aryl-H), 7.24 – 7.21 (m, 2H, aryl-H), 7.13 (t,
J = 8 Hz, 1H, aryl-H), 6.77 (d, J = 7.8 Hz, 1H, aryl-H), 6.72 (d, J = 8.3 Hz, 1H, aryl-H), 4.73 –
.64 (m, 2H, CH + NH), 4.24 – 4.14 (m, 2H, CH -O), 3.82 (s, 3H, OCH ), 3.35 (dd,
J = 3.3 Hz, 13.3 Hz, 1H, CHH-phenyl), 3.22 – 3.10 + 3.01 (m, 4H + m, 2H, CH -CH -CO +
4
2
3
2
2
CH -NH-Boc + CH -CO), 2.78 (dd, J = 9.8 Hz, 13.3 Hz, 1H, CHH-phenyl), 2.69 (t, J = 7.8 Hz,
2
2
13
2
H, CH
2
-CH
2
-CH
2
2 2
-NH-Boc), 1.77 (m, 2H, CH -CH -NH-Boc), 1.44 (s, 9H, t-Bu). C NMR
(
63 MHz, CDCl
3
): 173.0, 157.9, 156.0, 153.4, 141.1, 135.4, 129.4, 129.0, 127.3, 127.0,
1
26.7, 121.7, 108.2, 79.1, 66.2, 55.4, 55.3, 40.7, 38.0, 35.3, 31.7, 30.2, 28.4, 21.0. IR (neat):
3
1
8
369 (m), 2975 (w), 1791 (s), 1694 (s), 1684 (s), 1584 (m), 1530 (m), 1458 (m), 1394 (m),
368 (m), 1305 (m), 1264 (s), 1216 (s), 1168 (s), 1121 (m), 1104 (m), 1027 (m), 1007 (m),
64 (w), 797 (w), 776 (m), 757 (m), 733 (m), 695 (m), 643 (m), 550 (w), 532 (m), 506 (w).
20
mp: 97 – 100 °C. R
calcd for C H N O K [M+K] 535.2205: found 535.2197.
f
(n-hexane/EtOAc, 2:1) = 0.35. [D]
D
= -59.5° (c = 0.55, MeOH). HRMS:
+
28
36
2
6
1
4ꢀ
ꢀ

tert-Butyl N-[3-(2-{3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl}-3-(trifluoro
methyl)phenyl)propyl]carbamate (5d)
Following GP4 using methylester 3d (1.43 g; 2.93 mmol), Pd/C (286 mg), MeOH (30 mL);
NaOH (8 M; 19 mL), MeOH (19 mL); Piv-Cl (434 μL; 3.52 mmol), NEt (613 μL; 4.40 mmol),
3
dry THF (33 mL), (R)-4-benzyl-2-oxazolidinone (1.04 g; 5.86 mmol), n-BuLi (1.6 M in n-
hexane; 3.48 mL; 5.57 mmol), dry THF (16.5 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 3:1 Æ 1:1.
Yield: 1.06 g (68% over 3 steps); colourless solid after recrystallization from DCM/n-hexane.
1
H NMR (250 MHz, CDCl
.24 – 7.21 (m, 2H, aryl-H), 4.78 – 4.61 (m, 2H, CH + NH), 4.30 – 4.18 (m, 2H, CH
dd, J = 3.3 Hz, 13.3 Hz, 1H, CHH-phenyl), 3.26 – 3.09 (m, 6H, CH -CO + CH -CH
2
3
): 7.53 (d, J = 7.8 Hz, 1H, aryl-H), 7.39 – 7.29 (m, 5H, aryl-H),
-O), 3.36
-CO +
7
(
2
2
2
CH -NH-Boc), 2.84 (dd, J = 9.5 Hz, 13.3 Hz, 1H, CHH-phenyl), 2.71 (m, 2H, CH -CH -CH -
2
2
2
2
13
NH-Boc), 1.81 (m, 2H, CH
2
-CH
2
-NH-Boc), 1.44 (s, 9H, t-Bu). C NMR (63 MHz, CDCl
3
):
1
1
71.9, 156.0, 153.5, 142.2, 136.8, 135.2, 133.1, 129.4, 129.0, 127.4, 126.6, 124.4, 124.3,
19
22.6, 79.3, 66.4, 55.2, 40.5, 37.9, 36.5, 31.8, 29.5, 28.4, 23.4. F NMR (282 MHz, CDCl
3
):
-
(
(
(
59.2. IR (neat): 3675 (w), 3373 (w), 2988 (m), 1785 (m), 1711 (s), 1682 (s), 1524 (m), 1456
w), 1395 (m), 1373 (m), 1314 (m), 1298 (m), 1242 (m), 1210 (m), 1187 (m), 1151 (m), 1113
s), 1049 (s), 1009 (m), 977 (w), 879 (w), 797 (w), 763 (m), 735 (m), 700 (s), 590 (w), 508
20
w). mp: 91 – 94 °C. R
f
(n-hexane/EtOAc, 2:1) = 0.35. [D]
D
= -61.7° (c = 1.03, MeOH).
+
HRMS: calcd for C28
33
H F
3 2 5
N O K [M+K] 573.1973: found 573.1966.
tert-Butyl
N-[3-(2-{3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl}-3-phenyl
phenyl)propyl]carbamate (5e)
Following GP4 using methylester 3e (1.03 g; 2.08 mmol), Pd/C (206 mg), MeOH (21 mL);
NaOH (8 M; 15 mL), MeOH (15 mL); Piv-Cl (308 μL; 2.50 mmol), NEt (435 μL; 3.12 mmol),
3
dry THF (25 mL), (R)-4-benzyl-2-oxazolidinone (737 mg; 4.16 mmol), n-BuLi (1.6 M in n-
hexane; 2.47 mL; 3.95 mmol), dry THF (12.5 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 3:1 Æ 1:1.
Yield: 796 mg (71% over 3 steps); colourless oil.
1
H NMR (250 MHz, CDCl
.11 (m, 4H, aryl-H), 7.04 (m, 1H, aryl-H), 4.68 (br s, 1H, NH), 4.58 (m, 1H, CH), 4.20 – 4.09
m, 2H, CH -O), 3.28 – 3.17 (m, 3H, CH -NH-Boc + CHH-phenyl), 3.04 – 2.88 (m, 4H, CH
3
): 7.45 – 7.36 (m, 3H, aryl-H), 7.34 – 7.26 (m, 5H, aryl-H), 7.24 –
7
(
2
2
2
-
CH -CO + CH -CO), 2.76 – 2.67 (m, 3H, CH -CH -CH -NH-Boc + CHH-phenyl), 1.86 (m, 2H,
2
2
2
2
2
13
CH
2
-CH
2
-NH-Boc), 1.50 + 1.45 (s*, 9H, t-Bu). C NMR (63 MHz, CDCl
3
): 172.1, 156.0,
1
1
53.3, 143.1, 142.3, 140.1, 135.8, 135.2, 129.3, 129.1, 128.9, 128.7, 128.4, 128.1, 127.3,
26.8, 126.1, 79.1, 66.2, 55.0, 40.6, 37.8, 36.2, 31.9, 30.3, 28.4, 28.0, 23.7. IR (neat): 3389
(
(
m), 3060 (m), 3027 (m), 2976 (s), 2931 (s), 2869 (m), 1781 (s), 1698 (s), 1604 (w), 1583
w), 1516 (s), 1454 (s), 1391 (s), 1366 (s), 1303 (s), 1249 (s), 1213 (s), 1169 (s), 1108 (s),
1
5
C
074 (m), 1052 (m), 985 (m), 920 (w), 865 (w), 803 (w), 763 (s), 704 (s), 636 (w), 549 (w),
20
05 (w). R
(n-hexane/EtOAc, 2:1) = 0.40. [D]
= -39.1° (c = 1.06, DCM). HRMS: calcd for
f
D
+
H N O
33 38 2 5
K [M+K] 581.2412: found 581.2408.
1
5ꢀ
ꢀ

tert-Butyl N-[3-(1-{3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl}naphthalen-
-yl)propyl]carbamate (5f)
2
Following GP4 using methylester 3f (889 mg; 1.89 mmol), Pd/C (178 mg), MeOH (19 mL);
NaOH (8 M; 12 mL), MeOH (12 mL); Piv-Cl (280 μL; 2.27 mmol), NEt (396 μL; 2.84 mmol),
3
dry THF (24 mL), (R)-4-benzyl-2-oxazolidinone (670 mg; 3.78 mmol), n-BuLi (1.6 M in n-
hexane; 2.24 ml; 3.59 mmol), dry THF (12 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 3:1 Æ 1:1.
Yield: 628 mg (64% over 3 steps); colourless solid after recrystallization from DCM/n-hexane.
1
3
H NMR (250 MHz, CDCl ): 8.09 (d, J = 8.5 Hz, 1H, aryl-H), 7.81 (dd, J = 1 Hz, 8 Hz, 1H,
aryl-H), 7.69 (d, J = 8.5 Hz, 1H, aryl-H), 7.53 (m, 1H, aryl-H), 7.45 (m, 1H, aryl-H), 7.40 –
.29 (m, 4H, aryl-H), 7.25 – 7.23 (m, 2H, aryl-H), 4.77 – 4.68 (m, 2H, CH + NH), 4.25 – 4.17
m, 2H, CH -O), 3.50 (m, 2H, CH -NH-Boc), 3.38 (dd, J = 3.3 Hz, 13.3 Hz, 1H, CHH-phenyl),
.29 – 3.23 (m, 4H, CH -CH -CO + CH -CO), 2.92 – 2.78 (m, 3H, CH -CH -CH -NH-Boc +
7
(
2
2
3
2
2
2
2
2
2
13
CHH-phenyl), 1.87 (m, 2H, CH -CH -NH-Boc), 1.45 (s, 9H, t-Bu). C NMR (63 MHz, CDCl ) :
2
2
3
1
1
72.6, 156.0, 153.4, 137.2, 135.3, 132.8, 132.6, 132.1, 129.4, 129.0, 128.7, 128.1, 127.4,
27.1, 126.3, 124.9, 123.5, 79.1, 66.3, 55.3, 40.8, 38.0, 36.4, 32.0, 30.8, 28.4, 23.2. IR
(
(
(
(
neat): 3355 (m), 2972 (w), 1784 (s), 1699 (s), 1679 (s), 1522 (s), 1474 (m), 1442 (w), 1378
s), 1367 (s), 1347 (m), 1305 (m), 1268 (m), 1239 (m), 1208 (m), 1193 (s), 1171 (s), 1095
m), 1030 (m), 1018 (w), 1006 (s), 979 (m), 946 (w), 927 (w), 870 (w), 818 (m), 793 (w), 782
w), 764 (m), 752 (m), 738 (s), 705 (s), 671 (w), 613 (m), 579 (m), 565 (m), 503 (m). mp:
20
1
05 – 108 °C. R
f
(n-hexane/EtOAc, 2:1) = 0.35. [D]
D
= -58.8° (c = 0.50, MeOH). HRMS:
+
calcd for C31
36 2 5
H N O K [M+K] 555.2256: found 555.2249.
tert-Butyl N-[3-(1-{3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl}anthracen-2-
yl)propyl]carbamate (5g)
Following GP4 using methylester 3g (294 mg; 0.57 mmol), Pd/C (59 mg), MeOH/EtOAc (2:1;
8
0
mL); NaOH (8 M; 4 mL), MeOH (4 mL); Piv-Cl (84 μL; 0.68 mmol), NEt
.86 mmol), dry THF (7 mL), (R)-4-benzyl-2-oxazolidinone (202 mg; 1.14 mmol), n-BuLi
3
(120 μL;
(
1.6 M in n-hexane; 675 μL; 1.08 mmol), dry THF (3.5 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 3:1 Æ 1:1.
Yield: 114 mg (35% over 3 steps); yellow solid after recrystallization from DCM/n-hexane.
1
H NMR (250 MHz, CDCl
.98 (m, 1H, aryl-H), 7.86 (d, J = 8.8 Hz, 1H, aryl-H), 7.49 – 7.42 (m, 2H, aryl-H), 7.39 – 7.23
m, 6H, aryl-H), 4.79 – 4.70 (m, 2H, CH + NH), 4.26 – 4.17 (m, 2H, CH -O), 3.64 +
3
): 8.65 (s, 1H, aryl-H), 8.39 (s, 1H, aryl-H), 8.07 (m, 1H, aryl-H),
7
(
2
3
2
1
1
1
2
1
.43 – 3.22 (m, 2H + m, 5H, CH -NH-Boc + CHH-phenyl + CH -CH -CO + CH -CO),
2
2
2
2
.95 – 2.76 (m, 3H, CH
.45 (s, 9H, t-Bu). C NMR (63 MHz, CDCl
2
-CH
2
-CH
2
-NH-Boc + CHH-phenyl), 1.91 (m, 2H, CH
2
-CH
2
-NH-Boc),
13
3
): 172.7, 156.1, 153.4, 136.5, 135.3, 132.1,
32.0, 131.1, 130.9, 130.6, 129.4, 129.0, 128.7, 128.0, 127.7, 127.5, 127.4, 126.9, 125.34,
25.28, 122.1, 79.1, 66.3, 55.3, 40.7, 38.0, 36.3, 31.8, 31.0, 28.4, 23.5. IR (neat): 3367 (w),
966 (w), 1790 (s), 1698 (s), 1686 (s), 1537 (s), 1446 (w), 1394 (m), 1365 (m), 1292 (m),
269 (m), 1250 (m), 1211 (s), 1172 (s), 1121 (m), 1068 (w), 1032 (w), 1000 (m), 879 (m),
1
6ꢀ
ꢀ

7
60 (m), 737 (s), 724 (m), 701 (m), 643 (m). mp: 165 – 167 °C. R (n-hexane/EtOAc, 2:1) =
f
20
+
0
.35. [D]D = -50.0° (c = 0.21, DCM). HRMS: calcd for C H N O Na [M+Na] 589.2673:
35
38
2
5
found 589.2674.
tert-Butyl N-[3-(10-{3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl} phenan-
thren-9-yl)propyl]carbamate (5h)
Following GP4 using methylester 3h (1.38 g; 2.66 mmol), Pd/C (276 mg), MeOH/EtOAc (2:1;
2
6 mL); NaOH (8 M; 17 mL), MeOH (17 mL); Piv-Cl (393 μL; 3.19 mmol), NEt (556 μL;
3
3
.99 mmol), dry THF (30 mL), (R)-4-benzyl-2-oxazolidinone (943 mg; 5.32 mmol), n-BuLi
(
1.6 M in n-hexane; 3.16 mL; 5.05 mmol), dry THF (15 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 3:1 Æ 1:1.
Yield: 1.03 g (68% over 3 steps); colourless solid after recrystallization from DCM/n-hexane.
1
3
H NMR (250 MHz, CDCl ): 8.75 – 8.70 (m, 2H, aryl-H), 8.18 (m, 1H, aryl-H), 8.10 (m, 1H,
aryl-H), 7.70 – 7.60 (m, 4H, aryl-H), 7.40 – 7.25 (m, 5H, aryl-H), 4.87 (br s, 1H, NH), 4.77 (m,
H, CH), 4.29 – 4.18 (m, 2H, CH -O), 3.58 + 3.45 – 3.23 (m, 2H + m, 7H, CH -CH -CO +
1
2
2
2
CHH-phenyl + CH -CO + CH -NH-Boc + CH -CH -CH -NH-Boc), 2.86 (dd, J = 9.8 Hz,
2
2
2
2
2
13
1
3.5 Hz, 1H, CHH-phenyl), 1.94 (m, 2H, CH
2
2
-CH -NH-Boc), 1.47 (s, 9H, t-Bu). C NMR
(
63 MHz, CDCl ): 172.6, 156.1, 153.5, 135.3, 134.0, 131.5, 130.9, 130.8, 130.2, 130.0,
3
1
4
1
1
29.4, 129.0, 127.4, 127.0, 126.8, 125.9, 125.8, 124.5, 124.2, 123.1, 123.0, 79.2, 66.4, 55.3,
1.2, 38.0, 36.1, 31.1, 28.4, 26.5, 24.3. IR (neat): 3363 (w), 2977 (m), 1783 (s), 1760 (m),
707 (s), 1677 (s), 1509 (s), 1445 (m), 1394 (s), 1365 (s), 1271 (m), 1238 (m), 1208 (m),
186 (s), 1167 (s), 1120 (m), 1098 (m), 1047 (m), 993 (m), 977 (m), 864 (w), 752 (s), 735
(
m), 724 (s), 701 (m), 669 (w), 592 (m), 509 (w). mp: 166 – 168 °C. R
f
(n-hexane/EtOAc,
20
+
2
:1) = 0.30. [D]
D
= -63.6° (c = 0.50, DCM). HRMS: calcd for C35
38 2
H N O
5
K [M+K] 605.2412:
found 605.2409.
tert-Butyl
N-[3-(1-{3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl}pyren-2-
yl)propyl]carbamate (5i)
Following GP4 using methylester 3i (1.54 g; 2.83 mmol), Pd/C (308 mg), MeOH/EtOAc (1:2;
2
9 mL); NaOH (8 M; 18 mL), MeOH (18 mL); Piv-Cl (419 μL; 3.40 mmol), NEt (592 μL;
3
4
.25 mmol), dry THF (32 mL), (R)-4-benzyl-2-oxazolidinone (1.00 g; 5.66 mmol), n-BuLi
(
1.6 M in n-hexane; 3.36 mL; 5.38 mmol), dry THF (16 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 3:1 Æ 1:1.
Yield: 1.30 g (78% over 3 steps); colourless solid after recrystallization from DCM/n-hexane.
1
H NMR (250 MHz, CDCl ): 8.36 (d, J = 9.5 Hz, 1H, aryl-H), 8.18 – 8.12 (m, 3H, aryl-H),
3
8
4
CH
1
.04 – 7.94 (m, 4H, aryl-H), 7.39 – 7.23 (m, 5H, aryl-H), 4.86 – 4.71 (m, 2H, CH + NH),
.26 – 4.17 (m, 2H, CH -O), 3.76 3.43 – 3.30 (m, 2H + m, 5H, CH -CH -CO + CHH-phenyl +
-CO + CH -NH-Boc), 3.18 (m, 2H, CH -CH -CH -NH-Boc), 2.84 (dd, J = 9.8 Hz, 13.5 Hz,
H, CHH-phenyl), 2.03 (m, 2H, CH -CH -NH-Boc), 1.46 + 1.43 (s*, 9H, t-Bu). C NMR
2
2
2
2
2
2
2
2
1
3
2
2
(
63 MHz, CDCl
3
): 172.5, 156.1, 153.4, 138.0, 135.2, 132.3, 131.1, 130.4, 130.1, 129.4,
1
7ꢀ
ꢀ

1
1
2
1
29.3, 129.0, 127.9, 127.4, 127.2, 127.0, 126.2, 125.6, 125.0, 124.814, 124.805, 123.9,
23.2, 79.1, 66.4, 55.3, 40.8, 38.0, 37.0, 32.4, 31.3, 28.4, 26.9, 23.8. IR (neat): 3367 (w),
929 (w), 1793 (s), 1705 (s), 1677 (s), 1514 (s), 1394 (m), 1364 (m), 1296 (m), 1236 (m),
208 (m), 1189 (s), 1099 (m), 1044 (m), 1009 (m), 978 (m), 867 (w), 840 (m), 826 (m), 760
(
m), 749 (m), 736 (m), 701 (m), 683 (m), 592 (m), 506 (w). mp: 157 – 159 °C. R (n-
f
20
+
hexane/EtOAc, 2:1) = 0.30. [D]D = -54.2° (c = 0.20, DCM). HRMS: calcd for C H N O [M]
37
38
2
5
5
90.2775: found 590.2764.
General procedure for the conversion of carboximides 5a-i to the protected amino
acids (7a-i); GP5:
Carboximide 5a-i was dissolved in dry THF and cooled to -78 °C under an argon
atmosphere. In a second flask KHMDS (0.5 M in toluene; 2.5 equiv, for 5a 3.5 equiv) was
diluted in dry THF and cooled to -78 °C under an argon atmosphere. The KHMDS solution
was added to the carboximide and stirred at -78 °C for 30 min. Then a solution of tris-azide
(
1.5 equiv) in dry THF cooled to -78 °C was added. After 2 min at -78 °C the reaction was
quenched by addition of HOAc (4.6 equiv) and it was warmed to 30 °C in a water bath. After
h at 30 °C it was stirred at room temperature overnight.
3
For workup DCM was added and the organic layer was washed with brine. It was extracted
with DCM (3x) and washed with saturated NaHCO solution. After drying over MgSO the
crude product was purified by column chromatography (pentane/Et O 1:1 Æ 1:3).
3
4
2
The azide was dissolved in a THF/H
freshly pestled LiOH (2 equiv) were added. After 2.5 h at 0 °C the reaction was quenched
with an aq Na solution (4.4 equiv). Then it was acidified with HCl (4 M) at 0 °C,
extracted with EtOAc (3x), dried over Na SO and concentrated under reduced pressure.
2 2 2
O solution and cooled to 0 °C. H O (30%; 4 equiv) and
2 2 5
S O
2
4
The intermediate was dissolved in MeOH and treated with Pd/C (10% Pd basis, moistened
with water; 20 wt-%) under a H
over Celite .
2
atmosphere for 6 h. The catalyst was removed by filtration
®
After concentration under reduced pressure the amine was dissolved in a H
solution (1:1, v/v) and cooled to 0 °C. NaHCO (3 equiv) and a solution of Fmoc-OSu
1.1 equiv) in dioxane was added. Afterwards, the reaction mixture was stirred at room
temperature overnight.
2
O/dioxane
3
(
For workup it was acidified with HCl (1 M) under ice cooling and extracted with EtOAc (3x).
After drying over MgSO the protected amino acid was dissolved in dry DMF. NaHCO
2 equiv) and benzyl bromide (3 equiv) were added and the reaction mixture was stirred at
room temperature overnight.
4
3
(
H O was added and it was extracted with EtOAc (3x). The combined organic phases were
2
2 4
washed with H O (2x), dried over MgSO and purified by column chromatography.
1
8ꢀ
ꢀ

Benzyl (2R)-3-[2,6-bis(3-{[(tert-butoxy)carbonyl]amino}propyl)phenyl]-2-{[(9H-fluoren-
-ylmethoxy)carbonyl]amino}propanoate (7a)
9
Following GP5 using carboximide 5a (550 mg; 0.88 mmol), KHMDS (0.5 M in toluene;
.16 mL; 3.08 mmol), tris-azide (408 mg; 1.32 mmol), HOAc (232 μL; 4.05 mmol), dry THF
3 x 6 mL); isolated azide 6a (401 mg; 0.60 mmol); H O (30%; 245 μL; 2.40 mmol), LiOH
6
(
(
H
2
2
29 mg; 1.20 mmol), THF (9.2 mL), H
O); Pd/C (80 mg), MeOH (7 mL); Fmoc-OSu (223 mg; 0.66 mmol), NaHCO
.80 mmol), dioxane/H O (1:1; 4.7 mL), dioxane (2.3 mL); NaHCO (101 mg; 1.20 mmol),
BnBr (214 μL; 1.80 mmol), dry DMF (7 mL).
2
O (2.7 mL), Na
2
S
2
O
5
(502 mg; 2.64 mmol; in 1.9 mL
2
3
(151 mg,
1
2
3
Eluent for column chromatography: cyclohexane/EtOAc, 10:1 Æ 5:1 Æ 3:1.
Yield: 281 mg (40% over 5 steps); colourless solid after recrystallization from DCM/n-hexane.
1
H NMR (400 MHz, CDCl
.42 – 7.28 (m, 7H, aryl-H), 7.11 – 7.01 (m, 3H, aryl-H), 6.97 (d, J = 7.6 Hz, 2H, aryl-H), 5.55
d, J = 5.6 Hz, 1H, NH-Fmoc), 5.04 (d, J = 12 Hz, 1H, COO-CHH-phenyl), 4.97 (d, J =
2.4 Hz, 1H, COO-CHH-phenyl) 4.73 (m, 2H, NH-Boc), 4.56 (q, J = 8 Hz, 1H, D-CH), 4.40
m, 2H, CH -fluorenyl), 4.21 (m, 1H, CH-fluorenyl), 3.18 – 3.03 (m, 6H, D-CH-CH + CH -NH-
Boc), 2.70 – 2.55 (m, 4H, CH -CH -CH -NH-Boc), 1.71 (m, 4H, CH -CH -NH-Boc), 1.44 +
3
): 7.77 (d, J = 7.2 Hz, 2H, aryl-H), 7.61 – 7.58 (m, 2H, aryl-H),
7
(
1
(
2
2
2
2
2
2
2
2
13
1
1
1
3
.42 (s*, 18H, t-Bu). C NMR (75 MHz, CDCl ): 172.1, 156.0, 155.6, 143.8, 143.7, 141.3,
41.0, 134.7, 131.6, 128.6, 128.5, 128.3, 128.2, 127.7, 127.5, 127.2, 127.0, 125.1, 125.0,
20.0, 82.0, 79.0, 67.3, 66.9, 58.5, 54.7, 47.1, 40.4, 32.4, 31.8, 30.2, 28.4. IR (neat): 3356
(
(
m), 2979 (w), 1736 (m), 1684 (s), 1520 (s), 1451 (m), 1391 (w), 1366 (m), 1273 (s), 1254
s), 1239 (s), 1168 (s), 1106 (m), 1091 (m), 1033 (m), 997 (m), 872 (w), 782 (w), 757 (m),
7
39 (s), 695 (m), 621 (m), 543 (w). mp: 149 – 152 °C. R
f
(n-hexane/EtOAc, 2:1) = 0.35.
20
+
[
D]D = -3.1° (c = 0.77, DCM). HRMS: calcd for C H N O Na [M+Na] 814.4038: found
47
57
3
8
8
14.4063.
Benzyl
(2R)-3-[2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-6-methylphenyl]-2-{[(9H-
fluoren-9-ylmethoxy)carbonyl]amino}propanoate (7b)
Following GP5 using carboximide 5b (231 mg; 0.48 mmol), KHMDS (0.5 M in toluene;
2
.40 mL; 1.20 mmol), tris-azide (223 mg; 0.72 mmol), HOAc (126 μL; 2.21 mmol), dry THF (3
x 3 mL); isolated azide 6b (100 mg; 0.19 mmol); H (30%; 78 μL; 0.76 mmol), LiOH (9 mg;
.38 mmol), THF (2.9 mL), H O (0.9 mL), Na (160 mg; 0.84 mmol; in 0.6 mL H O);
Pd/C (20 mg), MeOH (2 mL); Fmoc-OSu (71 mg; 0.21 mmol), NaHCO (48 mg, 0.57 mmol),
2 2
O
0
2
S O
2 2 5
2
3
dioxane/H
2 3
O (1:1; 1.3 mL), dioxane (0.7 mL); NaHCO (32 mg; 0.38 mmol), BnBr (68 μL;
0
.57 mmol), dry DMF (2 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 10:1 Æ 5:1.
Yield: 56 mg (18% over 5 steps); colourless solid after recrystallization from DCM/n-hexane.
1
H NMR (400 MHz, CDCl
t, J = 7.2 Hz, 2H, aryl-H), 7.33 – 7.26 (m, 5H, aryl-H), 7.08 – 7.05 (m, 3H, aryl-H), 6.99 –
.96 (m, 2H, aryl-H), 5.47 (d, J = 7.6 Hz, 1H, NH-Fmoc), 5.07 (d, J = 12.4 Hz, 1H, COO-
CHH-phenyl), 5.00 (d, J = 12 Hz, 1H, COO-CHH-phenyl), 4.80 (br s, 1H, NH-Boc), 4.61 (q,
3
): 7.76 (d, J = 7.6 Hz, 2H, aryl-H), 7.58 – 7.52 (m, 2H, aryl-H), 7.40
(
6
1
9ꢀ
ꢀ

J = 8 Hz, 1H, D-CH), 4.36 (d, J = 6.8 Hz, 2H, CH -fluorenyl), 4.17 (t, J = 6.8 Hz, 1H, CH-
2
fluorenyl), 3.21 – 3.07 (m, 4H,ꢀD-CH-CH + CH -NH-Boc), 2.65 (m, 2H, CH -CH -CH -NH-
2
2
2
2
2
13
Boc), 2.30 (s, 3H, CH ), 1.72 (m, 2H, CH -CH -NH-Boc), 1.42 (s, 9H, t-Bu). C NMR
3
2
2
(
75 MHz, CDCl
3
): 172.2, 156.0, 155.6, 143.8, 143.7, 141.3, 140.7, 137.2, 134.8, 132.2,
1
4
1
1
9
28.6, 128.5, 128.3, 128.1, 127.7, 127.4, 127.0, 125.1, 120.0, 79.0, 67.3, 67.1, 54.0, 47.1,
0.5, 32.9, 31.8, 30.1, 28.4, 26.9, 20.3. IR (neat): 3356 (w), 2979 (w), 1757 (m), 1701 (s),
682 (s), 1528 (s), 1451 (m), 1390 (w), 1366 (m), 1263 (s), 1214 (m), 1168 (s), 1105 (m),
089 (m), 1040 (m), 991 (m), 874 (w), 756 (m), 738 (s), 698 (m), 621 (m), 541 (w). mp: 94 –
20
D
6 °C. R
f
(n-hexane/EtOAc, 2:1) = 0.40. [D]
= -6.8° (c = 0.22, DCM). HRMS: calcd for
+
C H N O Na [M+Na] 671.3092: found 671.3091.
40
44
2
6
Benzyl
(2R)-3-[2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-6-methoxyphenyl]-2-{[(9H-
fluoren-9-ylmethoxy)carbonyl]amino}propanoate (7c)
Following GP5 using carboximide 5c (433 mg; 0.87 mmol), KHMDS (0.5 M in toluene;
4
.36 mL; 2.18 mmol), tris-azide (405 mg; 1.31 mmol), HOAc (229 μL; 4.00 mmol), dry THF (3
x 6 mL); isolated azide 6c (273 mg; 0.51 mmol); H O (30%; 208 μL; 2.04 mmol), LiOH
2
2
(
24 mg; 1.02 mmol), THF (7.8 mL), H O (2.3 mL), Na S O (426 mg; 2.24 mmol; in 1.6 mL
2 2 2 5
H O); Pd/C (55 mg), MeOH (6 mL); Fmoc-OSu (189 mg; 0.56 mmol), NaHCO (129 mg,
2 3
1
.53 mmol), dioxane/H O (1:1; 4 mL), dioxane (2 mL); NaHCO (86 mg; 1.02 mmol), BnBr
2 3
(
182 μL; 1.53 mmol), dry DMF (6 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 10:1 Æ 5:1.
Yield: 83 mg (14% over 5 steps); colourless solid after recrystallization from DCM/n-hexane.
1
H NMR (400 MHz, CDCl ): 7.75 (d, J = 7.6 Hz, 2H, aryl-H), 7.55 – 7.50 (m, 2H, aryl-H), 7.39
3
(
t, J = 7.6 Hz, 2H, aryl-H), 7.34 – 7.25 (m, 7H, aryl-H), 7.16 (t, J = 8 Hz, 1H, aryl-H), 6.81 (d,
J = 7.6 Hz, 1H, aryl-H), 6.71 (d, J = 8.4 Hz, 1H, aryl-H), 5.79 (d, J = 7.2 Hz, 1H, NH-Fmoc),
.15 (s, 2H, COO-CH -phenyl), 4.67 (br s, 1H, NH-Boc), 4.49 (m, 1H, D-CH), 4.31 (m, 2H,
CH -fluorenyl), 4.16 (m, 1H, CH-fluorenyl), 3.78 (s, 3H, OCH ), 3.20 – 3.07 (m, 4H, D-CH-
CH + CH -NH-Boc), 2.65 (m, 2H, CH -CH -CH -NH-Boc), 1.73 (m, 2H, CH -CH -NH-Boc),
5
2
2
3
2
2
2
2
2
2
2
1
3
1
1
7
.43 (s, 9H, t-Bu). C NMR (75 MHz, CDCl ): 172.1, 157.8, 156.0, 155.8, 144.0, 143.8,
3
42.0, 141.3, 135.4, 128.5, 128.2, 128.0, 127.6, 127.0, 125.1, 122.9, 122.2, 119.9, 108.2,
9.1, 67.0, 66.9, 55.4, 54.8, 47.1, 40.5, 31.5, 29.8, 28.4. IR (neat): 3367 (w), 2962 (w), 1750
(
(
m), 1700 (m), 1677 (s), 1584 (w), 1519 (s), 1470 (m), 1448 (m), 1392 (w), 1363 (w), 1269
s), 1221 (m), 1163 (s), 1108 (m), 1097 (m), 1044 (m), 994 (w), 956 (m), 868 (w), 783 (m),
7
52 (m), 740 (s), 697 (m), 621 (m), 536 (m). mp: 143 – 146 °C. R
f
(n-hexane/EtOAc, 2:1) =
20
+
0
.35. [D]D = -4.4° (c = 0.46, DCM). HRMS: calcd for C H N O Na [M+Na] 687.3041:
40
44
2
7
found 687.3061.
Benzyl (2R)-3-[2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-6-(trifluoromethyl)phenyl]-2-
[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoate (7d)
{
Following GP5 using carboximide 5d (380 mg; 0.71 mmol), KHMDS (0.5 M in toluene;
.56 mL; 1.78 mmol), tris-azide (331 mg; 1.07 mmol), HOAc (187 μL; 3.27 mmol), dry THF (3
x 5 mL); isolated azide 6d (280 mg; 0.49 mmol); H O (30%; 200 μL; 1.96 mmol), LiOH
3
2
2
2
0ꢀ
ꢀ

(
23 mg; 0.98 mmol), THF (7.5 mL), H O (2.2 mL), Na S O (411 mg; 2.16 mmol; in 1.5 mL
2 2 2 5
H O); Pd/C (56 mg), MeOH (6 mL); Fmoc-OSu (182 mg; 0.54 mmol), NaHCO (123 mg,
2
3
1
.47 mmol), dioxane/H
2
O (1:1; 4 mL), dioxane (2 mL); NaHCO
3
(82 mg; 0.98 mmol), BnBr
(
175 μL; 1.47 mmol), dry DMF (6 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 10:1 Æ 5:1.
Yield: 232 mg (46% over 5 steps); colourless solid after recrystallization from DCM/n-hexane.
1
H NMR (400 MHz, CDCl
3
): 7.76 (d, J = 7.2 Hz, 2H, aryl-H), 7.55 (t, J = 8.4 Hz, 2H, aryl-H),
.42 – 7.28 (m, 9H, aryl-H), 7.22 (t, J = 8 Hz, 1H, aryl-H), 7.07 (m, 2H, aryl-H), 5.63 (d, J =
Hz, 1H, NH-Fmoc), 5.19 – 4.98 (m, 3H, COO-CH -phenyl + NH-Boc), 4.69 (q, J = 8 Hz, 1H,
-fluorenyl), 4.15 (t, J = 6.8 Hz, 1H, CH-fluorenyl), 3.36 – 3.20 (m, 4H,
D-CH-CH + CH -NH-Boc), 2.88 (m, 2H, CH -CH -CH -NH-Boc), 1.79 (m, 2H, CH -CH -NH-
7
8
2
D-CH), 4.33 (m, 2H, CH
2
2
2
2
2
2
2
2
1
3
Boc), 1.43 + 1.39 (s*, 9H, t-Bu). C NMR (75 MHz, CDCl ): 170.9, 156.1, 155.6, 143.8,
3
1
1
43.6, 143.2, 141.3, 134.7, 133.3, 132.5, 128.4, 128.3, 128.0, 127.7, 127.1, 127.0, 126.4,
19
25.1, 124.2, 120.0, 79.0, 67.3, 67.2, 54.1, 47.0, 40.4, 32.7, 31.7, 29.6, 28.4, 26.9. F NMR
): - 57.7. IR (neat): 3348 (m), 2973 (w), 1744 (m), 1681 (s), 1529 (s), 1451
m), 1367 (w), 1313 (m), 1253 (s), 1166 (s), 1115 (s), 1092 (m), 1045 (m), 1007 (m), 869
w), 782 (w), 756 (m), 739 (s), 696 (m), 621 (m), 542 (w). mp: 87 – 89 °C. R (n-
(
(
(
282 MHz, CDCl
3
f
20
D
hexane/EtOAc, 2:1) = 0.45. [D] = -1.9° (c = 0.37, DCM). HRMS: calcd for C H F N O Na
40 41
3
2
6
+
[
M+Na] 725.2809: found 725.2830.
Benzyl
(2R)-3-[2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-6-phenylphenyl]-2-{[(9H-
fluoren-9-ylmethoxy)carbonyl]amino}propanoate (7e)
Following GP5 using carboximide 5e (500 mg; 0.92 mmol), KHMDS (0.5 M in toluene;
4
.60 mL; 2.30 mmol), tris-azide (427 mg; 1.38 mmol), HOAc (242 μL; 4.23 mmol), dry THF (3
x 6 mL); isolated azide 6e (306 mg; 0.52 mmol); H O (30%; 212 μL; 2.08 mmol), LiOH
2
2
(
25 mg; 1.04 mmol), THF (8.0 mL), H O (2.3 mL), Na S O (435 mg; 2.29 mmol; in 1.6 mL
2 2 2 5
2 3
H O); Pd/C (61 mg), MeOH (6 mL); Fmoc-OSu (192 mg; 0.57 mmol), NaHCO (131 mg,
1
.56 mmol), dioxane/H O (1:1; 4 mL), dioxane (2 mL); NaHCO (87 mg; 1.04 mmol), BnBr
2 3
(
186 μL; 1.56 mmol), dry DMF (6 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 10:1 Æ 5:1.
Yield: 183 mg (28% over 5 steps); colourless solid after recrystallization from DCM/n-hexane.
1
H NMR (400 MHz, CDCl
3
): 7.77 – 7.76 (m, 2H, aryl-H), 7.53 – 7.49 (m, 2H, aryl-H), 7.43 –
.29 (m, 10H, aryl-H), 7.24 – 7.17 (m, 6H, aryl-H), 7.00 (d, J = 6.8 Hz, 1H, aryl-H), 5.03 (m,
H, COO-CH -phenyl), 4.80 (d, J = 8.4 Hz, 1H, NH-Fmoc), 4.68 (br s, 1H, NH-Boc), 4.35 –
7
2
4
3
2
.28 (m, 3H, D-CH + CH -fluorenyl), 4.12 (t, J = 6.8 Hz, 1H, CH-fluorenyl), 3.21 – 3.13 (m,
2
H, D-CH-CHH + CH -NH-Boc), 3.05 (m, 1H, D-CH-CHH), 2.76 (m, 2H, CH -CH -CH -NH-
2
2
2
2
13
Boc), 1.82 (m, 2H, CH -CH -NH-Boc), 1.44 (s, 9H, t-Bu). C NMR (75 MHz, CDCl ): 171.6,
2
2
3
1
1
7
1
1
56.0, 155.6, 143.9, 143.7, 143.6, 142.0, 141.3, 140.8, 135.1, 131.6, 129.5, 128.9, 128.5,
28.4, 128.3, 128.0, 127.68, 127.66, 127.1, 127.03, 127.00, 126.9, 125.00, 124.98, 119.9,
9.1, 67.0, 66.7, 54.9, 47.1, 40.5, 31.61, 31.57, 30.1, 28.4. IR (neat): 3355 (w), 2931 (w),
709 (s), 1506 (m), 1450 (m), 1391 (w), 1365 (m), 1336 (w), 1247 (m), 1166 (s), 1105 (w),
f
046 (m), 758 (s), 739 (s), 703 (m), 621 (w), 539 (w). mp: 55 – 57 °C. R (n-hexane/EtOAc,
2
1ꢀ
ꢀ

2
0
+
2
7
:1) = 0.45. [D]D = -2.1° (c = 0.28, DCM). HRMS: calcd for C H N O Na [M+Na]
45
46
2
6
33.3248: found 733.3247.
Benzyl
(2R)-3-[2-(3-{[(tert-butoxy)carbonyl]amino}propyl)naphthalen-1-yl]-2-{[(9H-
fluoren-9-ylmethoxy)carbonyl]amino}propanoate (7f)
Following GP5 using carboximide 5f (450 mg; 0.87 mmol), KHMDS (0.5 M in toluene;
4
.36 mL; 2.18 mmol), tris-azide (405 mg; 1.31 mmol), HOAc (229 μL; 4.00 mmol), dry THF (3
x 6 mL); isolated azide 6f (235 mg; 0.42 mmol); H (30%; 172 μL; 1.68 mmol), LiOH
20 mg; 0.84 mmol), THF (6.4 mL), H O (1.9 mL), Na S O (352 mg; 1.85 mmol; in 1.3 mL
2 2
O
(
2
2
2
5
2 3
H O); Pd/C (47 mg), MeOH (5 mL); Fmoc-OSu (155 mg; 0.46 mmol), NaHCO (106 mg,
1
.26 mmol), dioxane/H O (1:1; 3.3 mL), dioxane (1.7 mL); NaHCO (71 mg; 0.84 mmol),
2 3
BnBr (150 μL; 1.26 mmol), dry DMF (5 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 10:1 Æ 5:1.
Yield: 112 mg (19% over 5 steps); colourless solid after recrystallization from DCM/n-hexane.
1
3
H NMR (400 MHz, CDCl ): 8.09 (d, J = 8.8 Hz, 1H, aryl-H), 7.80 – 7.76 (m, 3H, aryl-H), 7.68
(
d, J = 8.4 Hz, 1H, aryl-H), 7.63 – 7.50 (m, 3H, aryl-H), 7.43 – 7.39 (m, 3H, aryl-H), 7.35 –
7
7
4
7
.29 (m, 3H, aryl-H), 7.24 – 7.19 (m, 3H, aryl-H), 6.83 (d, J = 6.8 Hz, 2H, aryl-H), 5.59 (d, J =
.6 Hz, 1H, NH-Fmoc), 4.95 (d, J = 12 Hz, 1H, COO-CHH-phenyl), 4.86 (br s, 1H, NH-Boc),
.72 (q, J = 7.6 Hz, 1H, D-CH), 4.64 (d, J = 12 Hz, 1H, COO-CHH-phenyl), 4.38 (d, J =
.2 Hz, 2H, CH -fluorenyl), 4.17 (t, J = 7.2 Hz, 1H, CH-fluorenyl), 3.66 – 3.52 (m, 2H, D-CH-
2
CH ), 3.19 (m, 2H, CH -NH-Boc), 2.82 (m, 2H, CH -CH -CH -NH-Boc), 1.79 (m, 2H, CH -
2
2
2
2
2
2
1
3
CH
2
3
-NH-Boc), 1.41 (s, 9H, t-Bu). C NMR (75 MHz, CDCl ): 172.1, 156.1, 155.6, 143.8,
1
1
3
43.7, 141.3, 138.5, 134.5, 132.8, 132.5, 128.7, 128.3, 128.2, 128.02, 127.97, 127.8, 127.7,
27.0, 126.5, 125.1, 125.0, 123.3, 119.9, 79.1, 67.4, 67.1, 54.7, 47.1, 40.5, 31.83, 31.78,
0.6, 28.4, 26.9. IR (neat): 3353 (m), 2972 (w), 1734 (m), 1683 (s), 1519 (s), 1451 (m), 1391
(
w), 1366 (m), 1273 (s), 1238 (s), 1168 (s), 1106 (m), 1090 (m), 1032 (m), 999 (m), 871 (w),
8
16 (w), 782 (w), 756 (m), 738 (s), 695 (m), 621 (m), 541 (w). mp: 121 - 124 °C. R
f
(n-
20
hexane/EtOAc, 2:1) = 0.35. [D]
D
= -8.6° (c = 0.30, DCM). HRMS: calcd for C43
44 2
H N O
6
Na
+
[
M+Na] 707.3092: found 707.3113.
Benzyl
(2R)-3-[10-(3-{[(tert-butoxy)carbonyl]amino}propyl)phenanthren-9-yl]-2-{[(9H-
fluoren-9-ylmethoxy)carbonyl]amino}propanoate (7h)
Following GP5 using carboximide 5h (600 mg; 1.06 mmol), KHMDS (0.5 M in toluene;
5
.30 mL; 2.65 mmol), tris-azide (492 mg; 1.59 mmol), HOAc (279 μL; 4.88 mmol), dry THF (3
x 7 mL); isolated azide 6h (414 mg; 0.68 mmol); H (30%; 278 μL; 2.72 mmol), LiOH
33 mg; 1.36 mmol), THF (10.4 mL), H O (3.1 mL), Na (568 mg; 2.99 mmol; in 2.1 mL
2 2
O
(
2
S O
2 2 5
H O); Pd/C (83 mg), MeOH (8 mL); Fmoc-OSu (253 mg; 0.75 mmol), NaHCO (171 mg,
2
3
2
.04 mmol), dioxane/H
2
O (1:1; 5.3 mL), dioxane (2.7 mL); NaHCO
3
(114 mg; 1.36 mmol),
BnBr (243 μL; 2.04 mmol), dry DMF (8 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 10:1 Æ 5:1.
Yield: 174 mg (22% over 5 steps); colourless solid after recrystallization from DCM/n-hexane.
2ꢀ
2
ꢀ

1
H NMR (400 MHz, CDCl
.8 Hz, 1H, aryl-H), 7.77 (d, J = 7.2 Hz, 2H, aryl-H), 7.66 – 7.57 (m, 6H, aryl-H), 7.42 – 7.39
m, 2H, aryl-H), 7.30 (t, J = 7.2 Hz, 2H, aryl-H), 7.12 (t, J = 7.2 Hz, 1H, aryl-H), 7.00 (t, J =
.6 Hz, 2H, aryl-H), 6.68 (d, J = 7.6 Hz, 2H, aryl-H), 5.70 (d, J = 5.2 Hz, 1H, NH-Fmoc), 5.02
br s, 1H, NH-Boc), 4.85 + 4.58 (m, 2H + m, 1H, COO-CH -phenyl + D-CH), 4.42 (m, 2H,
CH -fluorenyl), 4.19 (t, J = 6.8 Hz, 1H, CH-fluorenyl), 3.78 – 3.60 (m, 2H, D-CH-CH ), 3.40 –
3
): 8.73 – 8.69 (m, 2H, aryl-H), 8.19 (m, 1H, aryl-H), 8.03 (d, J =
6
(
7
(
2
2
2
3
1
1
1
5
1
1
.10 (m, 4H, CH -NH-Boc + CH -CH -CH -NH-Boc), 1.86 (m, 2H, CH -CH -NH-Boc), 1.47 +
2 2 2 2 2 2
13
3
.43 (s*, 9H, t-Bu). C NMR (75 MHz, CDCl ): 172.1, 156.1, 155.7, 143.8, 143.7, 141.3,
35.4, 134.2, 131.2, 130.7, 130.4, 129.9, 128.5, 128.2, 128.1, 127.9, 127.7, 127.6, 127.0,
26.8, 126.2, 125.9, 125.1, 124.8, 124.1, 123.1, 123.0, 120.0, 81.4, 79.1, 67.4, 67.2, 58.6,
4.6, 47.1, 40.8, 32.7, 30.8, 28.4, 26.5. IR (neat): 3346 (w), 2980 (w), 1733 (m), 1688 (s),
515 (s), 1447 (m), 1366 (w), 1343 (w), 1275 (s), 1238 (s), 1169 (s), 1085 (m), 1031 (m),
001 (m), 869 (w), 755 (s), 737 (s), 726 (s), 696 (m), 621 (m), 541 (w). mp: 184 – 186 °C. R
f
20
(
n-hexane/EtOAc, 2:1) = 0.35. [D]
D
= -3.8° (c = 0.42, DCM). HRMS: calcd for C47
H
46
2 6
N O Na
+
[
M+Na] 757.3248: found 757.3269.
Benzyl (2R)-3-[2-(3-{[(tert-butoxy)carbonyl]amino}propyl)pyren-1-yl]-2-{[(9H-fluoren-9-
ylmethoxy)carbonyl]amino}propanoate (7i)
Following GP5 using carboximide 5i (520 mg; 0.88 mmol), KHMDS (0.5 M in toluene;
4
.40 mL; 2.20 mmol), tris-azide (408 mg; 1.32 mmol), HOAc (232 μL; 4.05 mmol), dry THF (3
x 6 mL); isolated azide 6i (373 mg; 0.59 mmol); H (30%; 241 μL; 2.36 mmol), LiOH
28 mg; 1.18 mmol), THF (9.0 mL), H O (2.7 mL), Na (494 mg; 2.60 mmol; in 1.8 mL
2 2
O
(
2
2 2 5
S O
H O); Pd/C (75 mg), MeOH (7 mL); Fmoc-OSu (219 mg; 0.65 mmol), NaHCO (149 mg,
2
3
1
.77 mmol), dioxane/H
2
O (1:1; 4.7 mL), dioxane (2.3 mL); NaHCO
3
(99 mg; 1.18 mmol),
BnBr (211 μL; 1.77 mmol), dry DMF (7 mL).
Eluent for column chromatography: cyclohexane/EtOAc, 10:1 Æ 5:1.
Yield: 112 mg (17% over 5 steps); colourless solid after recrystallization from DCM/n-hexane.
1
3
H NMR (400 MHz, CDCl ): 8.70 (m, 1H, aryl-H), 8.33 (m, 1H, aryl-H), 8.20 – 8.10 (m, 2H,
aryl-H), 8.03 (m, 1H, aryl-H), 7.97 – 7.94 (m, 2H, aryl-H), 7.78 – 7.74 (m, 2H, aryl-H), 7.66 –
7
2
.54 (m, 3H, aryl-H), 7.40 – 7.37 (m, 2H, aryl-H), 7.32 – 7.22 (m, 2H, aryl-H), 7.14 – 6.98 (m,
H, aryl-H), 6.86 (m, 1H, aryl-H), 6.68 (d, J = 7.6 Hz, 1H, aryl-H), 6.53 (m, 1H, aryl-H), 5.69
(
2
m, 1H, NH-Fmoc), 4.97 – 4.80 + 4.67 (m, 3H + m, 1H, NH-Boc + COO-CH -phenyl + D-CH),
4
–
.42 (m, 2H, CH -fluorenyl), 4.18 (m, 1H, CH-fluorenyl), 3.95 – 3.60 (m, 2H, D-CH-CH ), 3.27
2
2
2 2 2 2 2 2
3.09 (m, 4H, CH -NH-Boc + CH -CH -CH -NH-Boc), 1.89 (m, 2H, CH -CH -NH-Boc), 1.43
13
(
s, 9H, t-Bu). C NMR (75 MHz, CDCl ): 172.0, 156.1, 155.6, 143.82, 143.78, 143.7, 141.3,
3
1
1
1
38.8, 131.1, 130.45, 130.39, 130.3, 129.9, 128.2, 128.0, 127.95, 127.86, 127.7, 127.3,
27.2, 127.0, 126.8, 126.3, 126.2, 125.9, 125.7, 125.2, 125.1, 124.9, 124.7, 123.7, 123.1,
23.0, 120.0, 79.1, 67.4, 67.1, 55.2, 54.6, 47.1, 40.6, 32.4, 31.0, 28.4, 26.9. IR (neat): 3344
(
w), 2980 (w), 1690 (s), 1517 (s), 1450 (m), 1366 (w), 1344 (w), 1267 (s), 1169 (s), 1087 (m),
1
1
032 (m), 871 (w), 841 (w), 827 (w), 755 (s), 738 (s), 696 (m), 621 (m), 541 (w). mp: 147 –
20
50 °C. R
f
(n-hexane/EtOAc, 2:1) = 0.35. [D]
D
= +4.5° (c = 0.31, DCM). HRMS: calcd for
+
C H N O Na [M+Na] 781.3248: found 781.3244.
49
46
2
6
2
3ꢀ
ꢀ

NMR spectra
1
ͲIodoͲ2Ͳphenylbenzeneꢀ(1e)ꢀ
I
ꢀ
I
ꢀ
ꢀ
ꢀ
ꢀ
2
4ꢀ

1
ͲIodonaphthaleneꢀ(1f)ꢀ
I
ꢀ
I
ꢀ
ꢀ
ꢀ
ꢀ
2
5ꢀ

AnthracenͲ1Ͳylꢀtrifluoromethanesulfonateꢀ(1g)ꢀ
O
S
O F
F
F
O
ꢀ
O
S
O F
F
F
O
ꢀ
ꢀ
ꢀ
ꢀ
2
6ꢀ

9
ͲIodophenanthreneꢀ(1h)ꢀ
I
ꢀ
I
ꢀ
ꢀ
ꢀ
ꢀ
2
7ꢀ

1
ͲIodopyreneꢀ(1i)ꢀ
I
ꢀ
I
ꢀ
ꢀ
ꢀ
ꢀ
2
8ꢀ

3
ͲIodoͲ1Ͳ[(4Ͳmethylbenzene)sulfonyl]Ͳ1HͲindoleꢀ(1j)ꢀ
I
N
S
O
O
ꢀ
I
N
S
O
O
ꢀ
ꢀ
ꢀ
2
9ꢀ