10.1002/cmdc.201700576
ChemMedChem
FULL PAPER
g) as a yellow powder. As this compound is not very stable, it was
immediately in the next step.
General procedure D – N-benzoylation of azetidinin-2-ones 10a-d
to 11a-d
General procedure B – Synthesis of azetidinones 9b-d
(3S,4R)-1-benzoyl-4-ferrocenyl-3-(triethysilyloxy)azetidin-2-one
((3S,4R)-11a): 302 µL (366 mg, 2.60 mmol) of freshly distilled benzoyl
chloride was added to a solution of 500 mg (1.30 mmol) of (3S,4R)-10a,
62 mg (0.51 mmol) of DMAP and 545 µL (396 mg, 3.91 mmol) of
triethylamine in 9 mL of DCM, and the resulting solution was stirred at
RT. After 2 h, the solvents were evaporated and the pure product was
isolated using column chromatography on silica gel 200 mL with n-
hexane/ethyl acetate (4:1) as the eluent. The pure product was isolated
as an orange solid in 93% yield (591 mg). This compound is not very
stable in solid state and in solution and was immediately used in the
next step. Due to low stability it was not possible to obtain good
elemental analysis and high quality NMR spectra. This compound was
used in the next step immediately.1H NMR (CDCl3) = 8.01 (d, J=7.4
Hz, 2H, Ph), 7.61 (t, J=7.5 Hz, 1H, Ph), 7.49 (t, J=7.7 Hz, 2H, Ph), 5.33
(d, J=6.4 Hz, 1H, H-4), 5.04 (d, J=6.4 Hz, 1H, H-3), 4.30-4.29 (m, 2H,
Cp), 4.21-4.19 (m, 7H, Cp), 0.94 (t, J=8.0 Hz, 9H, TES), 0.66-0.61 (m,
6H, TES); 13C{1H} NMR (CDCl3) = 166.6 (COPh), 166.1 (C-2), 133.4
(CHPh), 132.5(CPh), 130.2 (CHPh), 128.1 (CHPh), 82.6 (Cpipso), 76.2 (C-
4), 69.0 (Cp), 68.2 (Cp), 68.0 (Cp), 67.8 (Cp), 67.6 (Cp), 57.3 (C-3), 6.5
[ ]20
cis-4-(2-ferrocenylphenyl)-3-hydroxyazetidin-2-one (9b): 4.0
g
(15.3 mmol) of TBAF·3H2O was added to a solution of crude 8d in 20
ml of THF, and the resulting solution was stirred for 80 min at RT. After
addition of 100 mL of tert-butyl methyl ether and 50 mL of water, the
product was extracted with ethyl acetate. Chromatography on silica gel
(150 mL) using n-hexane/ethyl acetate (1:2), followed by
dichloromethane/ethyl acetate (1:1) gave 1.0 g of 9b as an orange solid.
1H NMR (DMSO-d6) = 8.27 (brs, 1 H, NH), 7.74 - 7.73 (m, 1H, Ph),
7.34 - 7.32 (m, 1H, Ph), 7.28 - 7.26 (m, 2H, Ph), 5.89 (d, J=7.6 Hz, 1H,
OH), 5.03 (d, J=4.8 Hz, 1H, H-3), 4.97 (ddd, J=7.5, 4.9, 2.5 Hz, 1H, H-
4), 4.55 - 4.53 (m, 1H, Cp), 4.41 - 4.40 (m, 1H, Cp), 4.38 - 4.37 (m, 1H,
Cp), 4.35 - 4.34 (m, 1H, Cp), 4.16 (s, 5H, Cp); 13C{1H} NMR (DMSO-
d6) = 170.1 (C-2), 137.4 (CPh), 135.3 (CPh), 130.3 (CHPh), 127.0 (CHPh),
126.5 (CHPh), 125.7 (CHPh), 86.2 (Cpipso), 79.7 (C-4), 70.9 (Cp), 69.2
(Cp), 68.3 (Cp), 68.2 (Cp), 67.9 (Cp), 55.4 (C-3); Elemental analysis for
C19H17FeNO2 Calculated C-65.73, H-4.94, N-4.03 found C-65.69, H-
4.93, N-3.95. Both enantiomers of 9b were separated using preparative
HPLC on a chiral semi-preparative column (Cellulose-1 10 × 250 mm)
using n-hexane/IPA (60:40) as the eluent at a flow rate of 10 mL/min.
(3S,4R)-9b eluted at =3.45 min and (3R,4S)-9b at =4.84 min. Both
isomers had the same NMR spectra as the racemic mixture of 9b.
[ ]20
(TES), 4.6 (TES);
푎
= -173.4 (CHCl3).
퐷
General procedure
paclitaxels
E – Synthesis of ferrocene-substituted
(3S,4R)-9b:
푎
= -247 (CHCl3), HPLC, Lux Cellulose-1, 4.6 mm ×
퐷
250 mm, hexane/IPA (50:50), 1 ml/min, 324 nm, optical purity 100% of
3’-dephenyl-3’-ferrocenyl-2’,7-O-bis(triethylsilyl)paclitaxel (12a):
A solution of 1.35 mL of LiHMDS (1M in THF, 1.35 mmol) was added
to a solution of 450 mg (0.92 mmol) of (3R,4S)-1-benzoyl-4-ferrocenyl-
3-(triethylilyloxy)azetidin-2-one (3R,4S)-11a and 430 mg (0.61 mmol)
of 7-triethylsilylbaccatin III 4 in 14.6 mL of anhydrous tetrahydrofurane
at -40 C and the resulting solution was stirred at this temperature for
40 min. After quenching of the reaction by addition of 50 mL of
saturated ammonium chloride, the product was extracted with ethyl
acetate. Chromatography on silica gel using n-hexane/ethyl acetate
(3:1) as eluent gave 591 mg (81%) of the desired product as a yellow
solid. 1H NMR (DMSO-d6) = 8.53 (d, J=9.8 Hz, 1H, NH), 8.05 (d, J=7.4
Hz, 2H, Ph), 7.94 (d, J=7.0 Hz, 2H, Ph), 7.70 (t, J=7.4 Hz, 1H, Ph),
7.58-7.51 (m, 5H, Ph), 6.29 (s, 1H, H-10), 6.01 (t, J=8.8 Hz, 1H, H-13),
5.46 (d, J=7.1 H, 1H, H-2), 5.33 (t, J=8.1 Hz, 1H, H-3’), 4.94 (d, J=9.6
Hz, 1H, H-5), 4.78 (s, 1H, 1-OH), 4.70 (s, 1H, Cp), 4.39 (dd, J=10.3, 6.8
Hz, 1H, H-7), 4.28 (d, J=6.7 Hz, 1H, H-2’), 4.24 (s, 1H, Cp), 4.17 (s, 1H,
Cp), 4.10 (s, 6H, Cp), 4.07 (d, J=8.3 Hz, 1H, H-20), 4.03 (d, J=8.2 Hz,
1H, H-20), 3.66 (d, J=7.1 Hz, 1H, H-3), 2.49-2.45 (m, 1H, H-6), 2.26 (s,
3H, 4-OCOCH3), 2.15 (dd, J=15.6, 9.2 Hz, 1H H-14), 2.10 (s, 3H, 10-
OCOCH3), 2.04 (dd, J=15.3, 9.2 Hz, 1H, H-14), 1.89 (s, 3H, H-18), 1.66
(brt, J=12.2 Hz, 1H, H-6), 1.55 (s, 3H, H-19), 1.07 (s, 6H, H-16 and H-
17), 0.86 (t, J=7.9 Hz, 9H, TES), 0.81 (t, J=7.9 Hz, 9H, TES), 0.56-0.45
(m, 12H, TES); 13C{1H} NMR (DMSO-d6) = 201.3 (C-9), 171.9 (C-1’),
169.8 (4-OCOCH3), 168.8 (10-OCOCH3), 166.6 (CONH), 165.1 (2-
OCOPh), 139.0 (C-12), 135.2 (CPh), 133.5 (C-11), 133.3 (CHPh), 131.0
(CHPh), 129.9 (CPh), 129.6 (CHPh), 128.5 (CHPh), 128.1 (CHPh), 127.4
(CHPh), 86.6 (Cpipso), 83.1 (C-5), 79.8 (C-4), 76.7 (C-1), 75.6 (C-2’), 75.3
(C-20), 74.6 (C-10), 74.3 (C-2), 71.9 (C-7), 70.1 (C-13), 68.3 (Cp), 67.8
(Cp), 67.6 (Cp), 67.2 (2xCp), 57.6 (C-8), 52.1 (C-3’), 45.9 (C-3), 42.9
(C-15), 36.6 (C-6), 34.9 (C-14), 26.2 (C-16 or C-17), 22.8 (4-OCOCH3),
21.0 (C-16 or C-17), 20.4 (10-OCOCH3), 13.8 (C-18), 9.7 (C-19), 6.4
(TES), 4.7 (TES), 4.1 (TES); MS (ESI) for C63H83FeNO14Si2 calculated
[ ]20
= +239CHCl3), HPLC, Lux
퐷
(-)-isomer, =7.18 min. (3R,4S)-9b:
푎
Cellulose-1, 4.6 mm × 250 mm, hexane/IPA (50:50), 1 ml/min, 324 nm,
optical purity 97.4 % of (+)-isomer, =9.02 min).
General procedure C - O-triethylsilylation of azetidinones 10a-d
cis-4-ferrocenyl-3-(triethylsilyloxy)azetidin-2-one (10a)
1.53 g (1.70 mL, 10.1 mmol) of TESCl was added to a solution of the
crude 9a (2.50 g, 6.49 mmol) in 80 mL of anhydrous pyridine, and the
resulting solution was stirred at RT for 50 min. Then 200 mL of water
was added and the product was extracted with ethyl acetate. The
organic phase was washed with water, brine and dried.
Chromatography on silica gel (250 mL) using n-hexane/ethyl acetate
(4:1) as the eluent gave 10a in 80% yield (2.84 g) as yellow crystals. 1H
NMR (DMSO-d6) = 8.41 (brs, 1H, NH), 4.82 (dd, J=4.4, 2.5 Hz, 1H,
H-4), 4.48 (d, J=4.6 Hz, 1H, H-3), 4.19 (s, 5H, Cp), 4.16 - 4.14 (m, 2H,
Cp), 4.14 (brs, 1H, Cp), 4.09 (s, 1H, Cp), 0.78 (t, J=8.0 Hz, 9H, TES),
0.47 - 0.34 (m, 6H, TES); 13C{1H} NMR (DMSO-d6) = 168.8 (C-2),
84.5 (Cpipso), 77.6 (C-4), 68.2 (Cp), 68.1 (Cp), 67.5 (Cp), 67.3 (Cp), 66.1
(Cp), 54.9 (C-3), 6.2 (TES), 4.0 (TES); Elemental analysis for
C19H27FeNO2Si Calculated C-59.22, H-7.06, N-3.63 found C-61.08, H-
7.08, N-3.50. Both enantiomers of 10a were separated using
preparative HPLC on a chiral preparative column (Cellulose-2 21.2 ×
150 mm) using acetonitrile/water (9:1) as the eluent at a flow rate of 25
mL/min. (3S,4R)-10a (1.25 g) eluted at =4.08 min and (3R,4S)-10a
(1.28 g) at =5.22 min. Both compounds had the same NMR spectra as
[ ]20
the racemic mixture of 10a. (3S,4R)-10a:
푎 퐷 = +275 (CHCl3); HPLC,
Lux Cellulose-2, 4.6 mm × 150 mm, n-hexane/IPA (70:30), 1 mL/min,
222 nm, optical purity 100% of (+)-isomer, =9.00 min. (3R,4S)-10a:
[ ]20
푎
= -267 (CHCl3); HPLC, Lux Cellulose-2, 4.6 mm × 150 mm, n-
퐷
[ ]20
= -13.7 (CHCl3).
퐷
+
1189.5 found 1189.4 (M );
푎
hexane/IPA (70:30), 1 mL/min, 222 nm, optical purity 98.1% of (-)-
isomer, =15.93 min.
General
procedure
F
–
Desilylation
of
O-2’,7-
bis(triethylsilyl)paclitaxels
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