Ethyl (2Z )-7-chloro-2-fluoro-6-oxohept-2-enoate 11
(4R,5S,4ЈR,5ЈS )-2,2Ј-cyclopropane-1,1-diylbis(4,5-diphenyl-4,5-
dihydro-1,3-oxazole) 26
To a solution of 1.0 g (4.68 mmol) of the diazoketone 2 in
10 mL of ether is added 9.36 mL (9.36 mmol) of 1.0 M HCl in
ether dropwise over 10 min. The reaction was stirred for 15 min
and the solvent was removed under reduced pressure. The
residue was chromatographed over silica gel, eluting with
10% EtOAc/hexanes to yield 0.99 g (95%) of the chloride 11
Following the general procedure described for the preparation
of 22, compound 26 was prepared from 2,2Ј-methylenebis-
[(4R,5S)-4,5-diphenyl-2-oxazoline to give 26 (23%) as a white
solid, mp 163–165 ЊC: 1H NMR (CDCl3, 400 MHz) δ 1.83 (m,
4H) 5.62 (d, 2H, J = 10.19 Hz), 5.98 (d, 2H, J = 10.24 Hz), 7.01
(m, 20H); 13C NMR (CDCl3, 100 MHz) δ 15.9, 19.02, 73.97,
86.18, 126.67, 126.97,127.42, 127.67, 127.69, 127.94, 128.13,
136.45, 137.79, 167.18. Anal. Calcd for C33H28N2O2.0.5H2O: C,
80.30; H, 5.92; N, 5.68. Found: C, 80.12; H, 5.66; N, 5.95%.
1
as a colorless oil: H NMR (CDCl3, 400 MHz) δ 1.33 (t, 3H,
J = 7.1 Hz), 2.55 (dq, 2H, J = 2.0, 7.3 Hz), 2.81 (t, 2H, J = 7.0
Hz), 4.08 (s, 2H), 4.26 (q, 2H, J = 7.1 Hz), 6.11 (dt, 1H, J = 32.9
and 7.7 Hz);13C NMR (CDCl3, 100 MHz) δ 14.1, 18.3 (d,
J = 3.3), 37.9 (d, J = 2.2 Hz), 47.8, 61.7, 117.9 (d, J = 11.0 Hz),
148.6 (d, J = 257.8 Hz), 160.3 (d, J = 35.3 Hz), 201.2; 19F NMR
(CDCl3, 376 Hz) δ Ϫ128.8.
Chiral HPLC analysis
Chiral HPLC analysis for %ee determination was performed on
an Agilent model 1100 HPLC instrument. Conditions: Chiral-
pak, AD-RH (Chiral Technologies, Inc., 5µm. 4.6 × 150 mm);
60% H2O/40% MeCN; 0.8 mL minϪ1 flow rate, 15 min.; 20 ЊC;
UV 200 nm.
Ethyl 6-methyl (2Z )-2-fluorohex-2-enedioate 12
A solution of 1.48 g (7.78 mmol) of the acid 9 in 10 mL of ether
was added dropwise over 15 min to a 0 ЊC solution of CH2N2 in
ether, which was prepared by treatment of a solution of 4.0 g
(38.8 mmol) of N-nitroso-N-methylurea in 40 mL of ether with
a solution of 10.9 g (19 mmol) of KOH pellets in 40 mL water.
The mixture was stirred for 1 h at 0 ЊC, and the solvent was
removed under reduced pressure to afford 1.53 g (96%) of the
methyl ester 12 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
δ 1.33 (t, 3H, J = 7.22 Hz), 2.47 (m, 2H), 2.55 (m, 2H),
3.70 (s, 3H), 4.27 (q, 2H, J = 7.22 Hz), 6.13 (dt, 1H, J = 7.6, 32.6
Hz); 13C NMR (CDCl3, 100 MHz) δ 14.3, 19.9 (d, J = 3.39 Hz),
32.7, 52.0, 61.4, 118.4 (d, J = 11.1 Hz), 148.8 (d, J = 258.3 Hz),
160.7 (d, J = 35.2 Hz), 172.8; 19F NMR (CDCl3, 376 MHz)
δ Ϫ129.2.
Chiral screening and method optimization
Chiral SFC screening was carried out using Berger Instruments
analytical supercritical fluid chromatographs fitted with six-
position column selection valves and Agilent model 1100 diode
array UV-Visible detectors. Chiral HPLC screening was carried
out using an Agilent model 1100 HPLC instrument fitted with a
well plate autosampler, a circular dichroism detector (Jasco, CD
1595) and a polarimetric detector (PDR Chiral, Advanced
Laser Polarimeter). Loading studies were performed with an
Agilent 1100 HPLC instrument fitted with a preparative
autosampler and a well plate fraction collector.
Ethyl (1S,5S,6S )-6-fluoro-2-oxobicycl[3.1.0]hexane-6-
carboxylate 1
Screening of adsorbents and reactive resins for selective removal
of chloroketone impurity, 11, from ketoester 1
To a solution of 16.9 mg (0.047 mmol) of Cu(OTf )2 in 39 mL
of 1,2-dichloroethane was added 31.2 mg (0.09 mmol) of (S)-
(Ϫ)-2,2Ј-isopropylidenebis(4-phenyl-4,5-dihydro-1,3-oxazole)
21 and the mixture was stirred for 1 h. The reaction was
brought to reflux, and a solution of 500 mg (2.33 mmol) of 2
in 8 mL of 1,2-dichloroethane was added dropwise over 2 h.
The reaction was cooled to room temperature, concentrated
under reduced pressure, and filtered over a plug of silica to
afford 0.34 g (80%) of 1 as a colorless oil: (ϩ1) [α]D ϩ0.104
Screening of adsorbents16 and reactive resins17 for selective
removal of chloroketone impurity, 11, from ketoester, 1, was
carried out as previously described 16,17 with analysis of treated
solutions using by HPLC (Chiralpak AD-H, 4.6 × 150 mm;
5%IPA/heptane @ 1.5 mL minϪ1; UV @ 200 nm.
Preparative chiral HPLC resolution of 1
Preparative chromatography was performed on a system con-
taining dual Varian SD-1 pumps (800 mL minϪ1), Varian 215
injector pump 100 mL minϪ1, Varian 320 variable wavelength
UV/VIS detector, R&S Techologies/Varian LC ReSonator
liquid handling module and control software, with a Prochrom/
Novasep dynamic axial compression (DAC) column (5 cm i.d.)
packed with Chiralpak AD (ca. 25 cm bed length). Initially, 26 g
of 1 was resolved using an eluent of 100% methanol at a flow
rate of 240 mL minϪ1 with detection at 220 nm using a typical
injection of 10 mL of an 80 mg mLϪ1 solution of 1 in methanol
to afford an overall productivity of about 0.5 kkd (kilograms of
purified enantiomer per kilogram of stationary phase per day).
Further method optimization studies using a 4.6 × 250 mm
column packed with 20 micron preparative Chiralpak AD
material led to the selection of 15% 2-propanol (IPA) in
heptane as the preferred eluent for preparative separation.
Loading studies with enantioenriched 1 (210 mg mLϪ1 in
eluent; 60% ee) afforded a productivity of 1.2 kkd.
1
(c 0.0055, CHCl3); H NMR (CDCl3, 400 MHz) δ 1.26 (t, 3H,
J = 7.2 Hz), 2.22 (m, 3H), 2.43 (m, 1H), 2.59 (d, 1H, J = 6.4 Hz),
2.67 (dt, 1H, J = 6.2 and 2.1 Hz), 4.25 (q, 2H, J = 7.2 Hz);
13C NMR (CDCl3, 100 MHz) δ 14.1, 19.6, 34.2 (d, J = 12 Hz),
35.6, 40.2 (d, J = 12 Hz), 62.5, 79.5 (d, J = 246 Hz), 167.1 (d,
J = 25 Hz), 208.9; 19F NMR (CDCl3, 376 MHz) δ Ϫ211.4.
(4S,4ЈS )-2,2Ј-Cyclopropane-1,1-diylbis(4-phenyl-4,5-dihydro-
1,3-oxazole) 22
To a Ϫ65 ЊC solution of 1.0 g (3.26 mmol) of 2,2Ј-methylene-
bis[(4S)-4-phenyl-2-oxazoline], 0.76 g (7.52 mmol) of TMEDA
and 0.33 g (3.26 mmol) of diisopropylamine in 46 mL THF was
added 2.6 mL (6.5 mmol) of 2.5M n-BuLi in hexanes. The solu-
tion was warmed to Ϫ25 ЊC for 20 min, then cooled to Ϫ65 ЊC
and 0.64 g (3.42 mmol) of 1,2-dibromoethane was added drop-
wise. The mixture was warmed to room temperature and stirred
for 12 h. The reaction was quenched with 25 mL of sat. NH4Cl
and diluted with 20 mL of MTBE. The layers were separated,
and the organic layer was concentrated. The crude residue
was purified by silica gel chromatography eluting with 70%
EtOAc/hexanes to afford 0.42 g (39%) of 22 as a light brown
References
1 A. Nakazato, T. Kumagai, K. Sakagami, R. Yoshikawa, Y. Suzuki,
S. Chaki, H. Ito, T. Taguchi, S. Nakanishi and S. Okuyama, J. Med.
Chem., 2000, 43, 4893.
2 T. Allmendinger, Tetrahedron, 1991, 47, 4905.
3 L. Skattebol, B. Boulette and S. Soloman, J. Org. Chem., 1967, 32,
3111.
1
oil: H NMR (CDCl3, 400 MHz) δ 1.59 (m, 4H), 4.17 (t, 2H,
J = 8.12 Hz), 4.69 (dd, 2H, J = 8.38, 10.06 Hz), 5.22 (dd, 2H
J = 7.63, 10.04 Hz), 7.30 (m, 10H); 13C NMR (CDCl3,
100 MHz) δ 16.0, 18.6, 69.6, 75.6, 126.8, 127.0, 127.7, 128.9,
128.9, 142.5, 167.1.
4 A. McKillop and J. A. Tarbin, Tetrahedron Lett., 1983, 24, 1505.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 6 8 – 1 7 4
173