Organic Process Research & Development
Article
It should be mentioned that the enantiomeric excess (green
line) did not change even after extended reaction times.
Although the durability test using 1-cis-OTMS showed a
similar trend, the reaction conversion was relatively low
compared with that of 1-cis-H, suggesting that steric hindrance
S4).14 It should be noted that increasing the catalyst loading
resulted in increased conversion in the case of 1-cis-OTMS
reaction conversion would be possible.
Investigation of Epimerization. Continuous-flow oper-
ation (as described in Table 3) shows an increase in
diastereoselectivity in line with a decrease in the residence
time as well as an increase in the flow rate. This suggests that
reducing the contact time of the reaction mixture with the
catalyst is important for high dr values. This can be partly
attributed to limiting the undesired epimerization of the
product by minimizing the exposure to the catalyst. In order to
investigate this epimerization effect, the dr value was evaluated
upon treatment with 1-cis-H in the batch system, as shown in
Figure 5 (see Table S14). In the presence of 1-cis-H and
to efficient synthesis of APIs, agrochemicals, etc. using these
catalysts in continuous-flow mode, and further investigation of
the substrate scope and scale-up application to specific APIs is
underway.
EXPERIMENTAL SECTION
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General Procedure for Asymmetric Michael Addition
of Butyraldehyde to Nitrostyrene. To a solution of trans-β-
nitrostyrene (3) (149 mg, 1.00 mmol, 1 equiv) in a solvent (5
mL) were added an acid (0.100 mmol, 0.10 equiv),
butyraldehyde (4) (361 mg, 5.00 mmol, 5.0 equiv), and a
polymer catalyst (0.0500 mmol, 5.0 mol %) at 25 °C. After 24
h of stirring at the same temperature, the reaction mixture was
filtered to remove the polymer catalyst. The eluent was
concentrated under reduced pressure to obtain the crude
mixture, which was purified by silica gel column chromatog-
raphy (5:1 n-Hex/EtOAc) to afford a diastereomixture of 2-
ethyl-4-nitro-3-phenylbutanal (5) as a colorless oil. The dr
value of 5 (syn-5:anti-5) was determined by 1H NMR
spectroscopyy (integration of peak area). The ee value of
syn-5 was determined by chiral HPLC.
General Procedure for Continuous-Flow Synthesis.
Preliminary Preparation. A mixture of 1-cis-H (0.100 mmol,
10 mol %) and sea sand was ground in a mortar and charged
into a glass column. CH2Cl2 (ca. 10 mL) was passed through
the packed-bed column for swelling of 1-cis-H in advance. The
temperature of the packed-bed column was controlled by a
column oven for HPLC.
Continuous-Flow Experiment. A solution of 3 (149 mg,
1.00 mmol, 1 equiv), benzoic acid (12.2 mg, 0.100 mmol, 10
mol %), and 4 (361 mg, 5.00 mmol, 5.0 equiv) in CH2Cl2 (5
mL) was passed through the packed-bed column at the
indicated flow rate and temperature. After the injection of the
substrate solution was complete, CH2Cl2 (5 mL) was passed
through the column at the same flow rate and temperature for
washout. The eluent was concentrated under reduced pressure
to obtain a crude mixture, which was purified by silica gel
column chromatography (5:1 n-Hex/EtOAc) to afford a
diastereomixture of 5 as a colorless oil. The dr value of 5
(syn-5:anti-5) was determined by 1H NMR spectroscopy
(integration of peak area). The ee value of syn-5 was
determined by chiral HPLC.
HPLC Method. High-performance liquid chromatography
(HPLC) was performed on an LC-2030 Plus chromatograph
with a YMC-triart C18 column (250 mm × 4.6 mm i.d.). The
column oven was set at 40 °C, and the UV detector was set at
210 nm. Mobile phases A (0.1% aqueous phosphoric acid) and
B (acetonitrile) were utilized at a flow rate of 1.5 mL/min.
Mobile phase B was increased linearly from 15% to 80% over
22.5 min and maintained at 80% for 5 min. Retention times: 3
(15.5 min), syn-5 (16.0 min), anti-5 (16.6 min).
Figure 5. Investigation of epimerization.
benzoic acid, the dr value of 5 decreased over time (red line).
On the other hand, in the absence of 1-cis-H, the dr value did
not decrease as expected (green line), suggesting that the
interaction of product 5 with the catalyst caused undesired
epimerization. The addition of butyraldehyde resulted in
partial restriction of undesired epimerization (blue line),
suggesting competitive enamine formation from butyraldehyde
and 1-cis-H.
CONCLUSION
Chiral HPLC Method. The optical purity (enantiomeric
excess) of 5 (syn isomer) was analyzed on an LC-2030 Plus
chromatograph with a Chiralpak OD-H column (250 mm ×
4.6 mm i.d.). The column oven was set at 25 °C, and the UV
detector was set at 215 nm. Isocratic flow (80:20 n-Hex/IPA)
at a flow rate of 0.8 mL/min was used. Retention times:
(2S,3R)-5 (17.7 min), (2R,3S)-5 (22.6 min).
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An array of polymer-supported cis-2,4-diphenylmethylpyrroli-
dine derivatives were designed and synthesized, with the cis
polymers showing higher diastereoselectivity and enantiose-
lectivity than the trans polymers using the asymmetric Michael
addition of butyraldehyde to trans-β-nitrostyrene as a model
reaction. It was also found that the polymer chain plays an
important role in the high selectivity. Moreover, expanded
investigation of these catalysts to a continuous-flow process
was explored and showed an improvement in durability and
increases in reaction rate diastereoselectivity compared with
the batch system results. These findings lend themselves well
1
syn-5. H NMR (CDCl3) δ 9.72 (dd, J = 2.6, 1.4 Hz, 1H),
7.36−7.27 (m, 3H), 7.19−7.17 (m, 2H), 4.72 (dd, J = 12.6, 4.9
Hz, 1H), 4.63 (dd, J = 12.6, 9.8 Hz, 1H), 3.80 (td, J = 9.8, 4.9
Hz, 1H), 2.71−2.66 (m, 1H), 1.55−1.46 (m, 2H), 0.83 (td, J =
7.5, 1.2 Hz, 3H). 13C NMR (CDCl3) δ 203.2 (1CH), 136.7
D
Org. Process Res. Dev. XXXX, XXX, XXX−XXX