Synthesis of optically pure 2-trifluoromethyl lactic acid by asymmetric hydroformylation

Article abstract of DOI:10.1021/jo400115r

By utilizing Rh catalysts ligated by the P-chirogenic ligands QuinoxP* and DuanPhos, 3,3,3-trifluoroprop-1-en-2-yl acetate could be hydroformylated and subsequently oxidized to yield enantiomerically pure 2-trifluoromethyllactic acid.

Full text of DOI:10.1021/jo400115r

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Note
The Synthesis of Optically Pure 2-Trifluoromethyl
Lactic Acid by Asymmetric Hydroformylation
Xiao Wang, and Stephen L. Buchwald
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400115r • Publication Date (Web): 11 Feb 2013
Downloaded from http://pubs.acs.org on February 17, 2013
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The Synthesis of Optically Pure 2-Trifluoromethyl Lactic Acid by
Asymmetric Hydroformylation
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Xiao Wang and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
Email: sbuchwal@mit.edu
ABSTRACT: By utilizing Rh catalysts ligated by the Pꢀchirogenic ligands QuinoxP* and DuanPhos,
3,3,3ꢀtrifluoropropꢀ1ꢀenꢀ2ꢀyl acetate could be hydroformylated and subsequently oxidized to yield
enantiomerically pure 2ꢀtrifluoromethyl lactic acid.
Trifluoromethylated compounds, including optically active ones, have received increasing attention in the
fields of synthetic and medicinal chemistry.1 The construction of trifluoromethylꢀsubstituted quaternary
stereogenic centers remains a formidable challenge in organic synthesis.2 Enantiomerically pure
2ꢀtrifluoromethyl lactic acid (TFMLA, 1), also known as the Soloshonok acid, serves as an important building
block for many active pharmaceutical ingredients in different therapeutic areas (Scheme 1).3 It is also used for
studying the different physical properties (in particular, sublimation behavior) between enantiomerically pure
compounds and their corresponding racemic counterparts.4 The largeꢀscale synthesis of 1 normally involves a
Znꢀmediated asymmetric addition reaction of a methyl Grignard Reagent to 2,2,2ꢀtrifluoropyruvate, providing
1 with an enantiomeric excess of 50%. The enantiomerically pure compound is derived from the crude product
by resolution.5 Shaw has reported a process that employed the addition of cyanide to trifluoroacetone, followed
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by an enzymatic resolution of the racemic adduct.6 However, an efficient enantioselective synthesis of this
valuable molecule is highly desirable.
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Scheme 1. TFMLA (1) as an important chiral building block of drug candidates.
O
Me
HN
OBut
Me
O
N
N
Me
HN
Me
CF3
OH
F
O
N
HO Me
H
N
N
CF3
O
F
F
F
O
Cl
F
BACE1 inhibitor
Bradykinin Antagonist (Merck)
Anti-inflammatory and painkiller
(Hoffmann-La Roche and Siena Biotech)
For treating Alzheimer's disease
O
O
S
O
O
S
O
Et
NH
F3C
F3C
N
N
Me OH
S
O
H
Me OH
Cl
N
O
Me
Pyruvate dehydrogenase
Putative afferent nerve inhibitor
(Kyowa Hakko Kogyo)
For treating urinary incontinence
kinase inhibitor (AstraZeneca)
For treating type II diabetes
An attractive alternative route to access 1 would be the asymmetric hydroformylation (AHF)7,8 of
1ꢀ(trifluoromethyl)ethenyl acetate (3), a relatively inexpensive precursor. During the course of our study on the
AHF of 1,1ꢀdisubstituted olefins,9 we were surprised to observe that the AHF of 3 was selective for the
branched product 2 (disfavored by Keulemans’ rule).10 Compound 2 could be oxidized to afford 1 (Scheme 2).
We thus sought to optimize our initial result with the intent of realizing an efficient and industriallyꢀrelevant
process for the preparation of 1. While vinyl acetate is one of the most widely examined substrates in previous
studies of hydroformylation,8c,d the AHF of 3 has not been disclosed. In fact, to the best of our knowledge, the
only AHF of 1,1ꢀdisubstituted olefins reported to provide exclusively branched aldehyde products was with
α,β
ꢀdehydroamino acid esters as substrates, and proceeded with low levels of enantioselectivity.11 Herein we
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report the results of a study of the AHF of 3 to provide 2, which constitutes the first example of an AHF that
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forms a quaternary stereogenic center with high enantioselectivity.
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Scheme 2. Synthesis of TFMLA via an asymmetric quaternary-selective hydroformylation.
CHO
Me CHO
R1 R2
CO/H2
[Rh]
CO/H2
[Rh]
R1
R2
R1
R2
conventional
linear-selectivity
unconventional
branched-selectivity
1,1-disubstituted
olefins
F3C OH
F3C OAc
AHF
F3C
OAc
Me
Me
COOH
(TFMLA)
CHO
1
2
3
We began our work by evaluating a variety of chiral ligands for the AHF of 3; the representative results are
summarized in Scheme 3.12 Diazaphospholane (L4), which was reported to be highly selective in the AHF of a
broad range of monosubstituted olefins,8c,d gave the product in 66% ee. Three representative ligands from the
DuPhos, FerroTANE and BPE families were also examined (L5, L6 and L7). One of these, PhꢀBPE (L7), was
found to provide the best results among all traditional AHF ligands, providing 2 in high yield with an ee of
84%. However, Pꢀchirogenic ligands such as QuinoxP* (L8), BenzP* (L9) and DuanPhos (L10) provided the
best results, giving the desired product with ee’s of 92%, 88% and 92%, respectively. Similar to the AHF of
α
ꢀalkylacrylates that we recently reported,9 we believe that the Pꢀchirality is a critical feature for catalysts
derived from bidentate phosphorus ligands to achieve high enantioselectivity in the AHF of 3, since the chiral
pocket is more confined and closer to the reaction site as compared to traditional ligands.13
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Scheme 3. Ligand evaluation for the AHF of 3,3,3-trifluoroprop-1-en-2-yl acetate (3).
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Yield ee
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Ligand
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a GC yields are reported. The ee values were determined by chiral GC. The absolute configuration of 2 was determined by
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converting it to the methyl ester of 1 (see the experimental section).
To further investigate the cause of the unconventional regioselectivity in the AHF of 3, the hydroformylation
of 2ꢀpropenyl acetate (4) was conducted under the same conditions as in Scheme 3. Linear aldehyde 6 was
found to be the major product (Scheme 4). The most likely reason for the reversal of regioselectivity in the
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hydroformylation of 3 is the presence of the strongly electronꢀwithdrawing trifluoromethyl group, which
favors the branched intermediate (7) relative to the linear isomer (8). The well known effect of
electronꢀwithdrawing substituents to alter the regiochemical control in e.g., the hydroformylation of vinyl
acetate, is in accord with this result.8c,d We also observed that the overall yield of aldehyde products (5 and 6)
was much lower than that of 2 with the same ligands.14
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Scheme 4. The hydroformylation of 2-propenyl acetate (4).
The influence of reaction conditions on the yield and enantioselectivity of 2 was next explored using L8.
Using 1 mol% of catalyst, we observed a negative correlation between the concentration of the precatalyst and
the yield of 2 as well as the conversion of 3, over the range of 5−25 mmol/L (Scheme 5), although the ee
remained relatively constant over the same concentration range. We reasoned that at higher concentration, the
aggregation of the [Rh(QuinoxP*)acac] precatalyst is responsible for its lowered catalytic activity, thus leading
to lower conversion and yield.15 An evaluation of different L/Rh ratios was also performed, since it has been
reported by Landis that this ratio is often a crucial factor in the reproducibility of rhodiumꢀcatalyzed
hydroformylations.8d We found that the L/Rh value had a profound impact on the yield of product although,
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again, the ee remained largely unaffected (Scheme 6). Finally, the temperature dependence of this
transformation was examined. The product yield increased up to 90 °C, at which point it decreased
dramatically with an increase in the formation of side products, such as the hydrogenation product of 3. The
temperature has only a small effect on the enantioselectivity of the process, diminishing only slightly (3%) on
going from 80 to 100 °C.
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Scheme 5. Effect of precatalyst concentration.
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Yield
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ee
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Conversion
0
0.005
0.01
0.015
0.02
0.025
Concentration of [Rh(QuinoxP)acac] (mol/L)
Reaction conditions: CO/H2 (10 bar, 1:1), Rh(CO)2acac (1.0 mol%), (R,R)ꢀQuinoxP* (1.5 mol%), toluene, 95 °C, 8 h.
Scheme 6. Effect of L/Rh ratio.
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Yield
ee
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2.5
L/Rh
Reaction conditions: CO/H2 (10 bar, 1:1), Rh(CO)2acac (1.0 mol%), (R,R)ꢀQuinoxP* (1.1−2.5 mol%), toluene, 92 °C, 8 h.
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Scheme 7. Effect of reaction temperature.
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T (°C)
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Reaction conditions: CO/H2 (10 bar, 1:1), Rh(CO)2acac (1.0 mol%), (R,R)ꢀQuinoxP* (2.0 mol%), toluene, 8 h.
On a larger scale (10 mmol), a considerable pressure drop was observed during the course of the reaction.
Thus, it was necessary to use a higher initial pressure than when the reaction was performed on a 1 mmol scale.
Unfortunately, the L8-derived catalyst lost activity at the elevated pressure. For most rhodium catalysts, a
higher CO partial pressure leads to a lower overall reaction rate.16 In order to overcome this, we examined
other catalysts and found that the [Rh(DuanPhos)] catalyst worked well at higher pressures. The influence of
the syngas pressure was further explored, and we found that ee of the product increased slightly with
increasing pressure, while the yield was maximum at approximately 23 bar (Scheme 8).
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Scheme 8. Effect of syngas pressure.
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Yield
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Syngas Pressure (bar)
Reaction conditions: CO/H2 (1:1), Rh(CO)2acac (0.4 mol%), (R,R,S,S)ꢀDuanPhos (0.6 mol%), toluene, 110 °C, 18 h.
Having identified ligands and the corresponding reaction conditions for the AHF, we sought to develop a
concise twoꢀstep sequence to prepare 2ꢀtrifluoromethyl lactic acid (1) (Table 1). On a small scale (1 mmol), the
reaction of 3 with CO and H2 (10 bar) in the presence of 1.0 mol% Rh(CO)2acac and 2.5 mol% QuinoxP* (L8)
at 85 °C in toluene provided aldehyde 2 with 91% ee, which was immediately oxidized by NaClO2 and
saponified with NaOH to yield 1, after acidification and crystallization (46% yield (two steps), >99% ee). For a
larger scale reaction (10 mmol), DuanPhos (L10, 0.6 mol%) was employed with a reduced amount of
Rh(CO)2acac (0.4 mol%), and the AHF was carried out at 110 °C and 31 bar to give 1 after oxidation and
purification (52% overall yield, >99% ee).
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Table 1. A concise one-pot synthesis of chiral acid 1.
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Rh
%
L
P
T
time
(hr)
ee
Yield
ee
Scale
L
(bar) a
(°C)
[2]
[1]b
[1]c
(mmol)
%
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0.4
2.5
0.6
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31
85
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92
46
52
>99
>99
L8
10
110
18
L10
a The pressure before the reaction. b Twoꢀstep isolated yield (average of two runs). c Determined by chiral GC.
In conclusion, we have developed the first example of a highly enantioselective, quaternaryꢀselective
hydroformylation process. By utilizing Rh catalysts ligated by the Pꢀchirogenic ligands QuinoxP* and
DuanPhos, 1,1ꢀdisubstituted alkenyl ester 3 could be converted to the corresponding branched aldehyde 2 with
high enantioselectivity. Notably, the aldehyde product could be subsequently subjected to a series of
transformations, which yield optically pure 2ꢀtrifluoromethyl lactic acid 1 in a oneꢀpot fashion on large scale.
EXPERIMENTAL SECTION
General Information. Hydroformylation reactions were set up in a CAT24 autoclave from HEL Inc., or a
Parr reactor (model# 4564), and were stirred with a teflonꢀcoated magnetic stir bar. Caution: Reactions
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employing elevated pressure should be carried out in suitable equipment behind a blast shield and with
all appropriate precautions. Rh(CO)2acac and ligands were purchased from Strem Chemical Co.
3,3,3ꢀTrifluoropropꢀ1ꢀenꢀ2ꢀyl acetate (3) was purchased from Alfa Aesar. The syngas (1:1 mixture of CO/H2)
was purchased from Airgas. Caution: Syngas is flammable. Carbon monoxide is toxic and all
hydroformylation reactions should be carried out in a well ventilated fume hood. All reagents from
commercial sources were used as received. Flash chromatography was performed with silica gel from
American International Chemical, Inc. (40ꢀ63 Micron). New compounds (2 and the synthetic 1) were
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1
characterized by H, 13C, and 19F NMR, IR spectroscopy and high resolution mass spectroscopy (see the
Supporting Information for copies of NMR spectra).
(S)-1,1,1-trifluoro-2-methyl-3-oxopropan-2-yl acetate (2). In a 2 mL reaction vial (from HEL Inc., made
for the CAT24 reactor), 3,3,3ꢀtrifluoropropꢀ1ꢀenꢀ2ꢀyl acetate (3) (77 mg, 0.50 mmol), Rh(CO)2acac (1.3 mg,
0.0050 mmol) and (R,R)ꢀQuinoxP* (2.5 mg, 0.0075 mmol) were dissolved in anhydrous toluene (0.10 mL).
The reaction vial was placed in a HELꢀCAT24 reactor, which was pressurized with 10 bar of CO and H2 (1:1),
and heated to 90 ºC while stirring at 700 rpm. The reaction was stopped after 20 h by cooling the reactor in an
ice bath for 15 min followed by slowly venting the system. The mixture was analyzed by chiral GC. The
product was purified by flash chromatography (pentane/Et2O, 100:1 to 4:1 gradient elution) to afford the title
compound (31 mg, 34%; material loss due to volatility) as a colorless oil: Enantiomeric excess (92%) was
determined by chiral GC analysis [CP ChirasilꢀDex CD, 25 m × 0.25 mm × 0.25 mm, flow rate 3.5 mL/min,
25
method: ramp from 50 °C to 130 °C at 2.0 °C/min, 130 °C for 5 min: (S) tr = 4.0 min, (R) tr = 4.3 min)]; [α]D
+62 (c 0.42, CHCl3); 1H NMR (600 MHz, CDCl3) δ 9.51 (quasiꢀd, J = 1.0 Hz, 1H), 2.23 (s, 3H), 1.68 (s, 3H);
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13C NMR (150 MHz, CDCl3) δ 190.5 (d, J = 6.0 Hz), 169.3 (s), 122.5 (q, J = 283.5 Hz), 82.2 (q, J = 28.5 Hz),
20.6 (s), 13.8 (t, J = 31.5 Hz); 19F NMR (282 MHz, CDCl3) δ –77.1 (s, 3F); IR (thin film) 2965, 1762, 1734,
1653, 1457, 1387, 1303, 1237, 728, 668 cm–1; HRMS (DART, TOF) m/z [M + H]+ calcd for C6H8F3O3:
185.0426, found 185.0428.
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(S)-2-Trifluoromethyl lactic acid (1). Small scale synthesis: In a 2 mL reaction vial (from HEL Inc., made
for the CAT24 reactor), 3,3,3ꢀtrifluoropropꢀ1ꢀenꢀ2ꢀyl acetate (3) (154 mg, 1.0 mmol), Rh(CO)2acac (2.6 mg,
0.010 mmol) and (R,R)ꢀQuinoxP* (8.4 mg, 0.025 mmol) were dissolved in anhydrous toluene (1.5 mL). The
reaction vial was placed in a HELꢀCAT24 reactor, which was pressurized with 10 bar of CO and H2 (1:1), and
heated to 85 ºC while stirring at 700 rpm. The reaction was stopped after 8 h by cooling the reactor in an ice
bath for 15 min followed by careful venting of the system. The mixture was analyzed by chiral GC. A solution
of sodium chlorite (141 mg of commercial 80 w%, 1.25 mmol) in pH 3.5 buffer (2.0 mL) was added dropwise
to the combined solution of the crude AHF reaction mixture and 2ꢀmethylꢀ2ꢀbutene (2.0 M in THF, 5.0 mL,
10.0 mmol) in tertꢀbutyl alcohol (5.0 mL) at room temperature. The reaction progress was monitored by TLC.
After 10 h, NaOH (0.40 g) was added and the mixture was stirred for 3 h. At this time, aqueous HCl (3 M) was
added dropwise to the mixture until pH = 1. The layers were separated and the aqueous layer was extracted
with EtOAc (20 mL × 5). The combined organic layers were concentrated and the crude product was isolated
by flash chromatography (hexanes/EtOAc, 4:1 to 0:100 gradient elution) as a yellowish crystal. Rinsing the
crude product with cold pentane (0 ºC, 2.0 mL × 2, removed by decanting) afforded 1 (73 mg, 46%, two steps)
as white crystals: The absolute configuration was later confirmed as (S) by converting it to its methyl ester; mp
= 101–104 ºC; [α]D25 –687 (c 0.47, MeOH); 1H NMR (600 MHz, MeODꢀd4) δ 1.54 (quasiꢀq, J = 0.6 Hz, 3H);
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13C NMR (150 MHz, MeODꢀd4) δ 172.4 (s), 125.9 (q, J = 283.5 Hz), 76.1 (q, J = 28.5 Hz), 20.4 (q, J = 1.5
Hz); 19F NMR (282 MHz, MeODꢀd4) δ –81.4 (s, 3F); IR (thin film) 3412, 1735, 1458, 1291, 1169, 1102 cm–1;
HRMS (ESI, TOF) m/z [M – H]+ calcd for C4H4F3O3: 157.0113, found 157.0116.
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Larger scale synthesis of 1: In a Parr reactor (model# 4564), 3,3,3ꢀtrifluoropropꢀ1ꢀenꢀ2ꢀyl acetate (3) (1.54
g, 10.0 mmol), Rh(CO)2acac (10.6 mg, 0.041 mmol) and (R,R,S,S)ꢀDuanPhos (22.1 mg, 0.058 mmol) were
dissolved in anhydrous toluene (3.0 mL). The reactor was pressurized with 26 bar of CO and H2 (1:1), and
heated to 110 ºC (the pressure increased to 31 bar) while stirring at 700 rpm. The reaction was stopped after 18
h (the pressure had decreased to 23 bar) by cooling the reactor in an ice bath for 15 min followed by slowly
venting the system. The mixture was analyzed by chiral GC. A solution of sodium chlorite (1.41 g of
commercial 80 w%, 12.5 mmol) in pH 3.5 buffer (20 mL) was added dropwise to the combined solution of the
crude AHF reaction mixture and 2ꢀmethylꢀ2ꢀbutene (2.0 M in THF, 50 mL, 100 mmol) in tertꢀbutyl alcohol
(50 mL) at room temperature. The reaction progress was monitored by TLC. After 10 h, NaOH (4.0 g) was
added and the mixture was stirred for 3 h. At this time, aqueous HCl (3 M) was added dropwise to the mixture
until pH = 1. The layers were separated and the aqueous layer was extracted with EtOAc (200 mL × 5). The
combined organic layers were concentrated and the crude product was isolated by flash chromatography
eluting with hexanes/EtOAc (2:1) as a yellowish crystal. Rinsing the crude product with cold 4:1
pentane/CH2Cl2 mixture (0 ºC, 10 mL × 2, removed by decanting) afforded 1 (0.82 g, 52%, two steps) as white
crystals.
Determination of the absolute configuration of the aldehyde product. A combination of methanol (13
ꢀ
L, 0.32 mmol), DMAP (1.0 mg, 0.0082 mmol) and EDCI (15 mg, 0.078 mmol) was added to the solutions of
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racemic, (R)ꢀ and synthetic 2ꢀtrifluoromethyl lactic acid (1) (10 mg each, 0.063 mmol) in CH2Cl2 (2.0 mL
each). The solutions were stirred for 2 h at room temperature and monitored by TLC and GC. Each reaction
mixture was filtered through a thin layer of silica gel, and the filtrate was analyzed by chiral GC [CP
ChirasilꢀDex CD, 25 m × 0.25 mm × 0.25 mm, flow rate 3.5 mL/min, method: ramp from 50 °C to 130 °C at
4.0 °C/min, 130 °C for 25 min: (S) tr = 10.7 min, (R) tr = 10.9 min)]; the absolute configuration of the synthetic
sample of 1 was determined as (S) with an enantiomeric excess of >99%.
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AUTHOR INFORMATION
Corresponding Author
*Email: sbuchwal@mit.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank Novartis International AG (Basel, Switzerland) for financial support of this project, and Nippon Chemical
for additional support. We thank Prof. Clark Landis for the sample of the diazaphospholane ligand. We are grateful
to Drs. Timothy Noël, Meredeth McGowan and Christine Nguyen for their help with the preparation of this
manuscript.
ASSOCIATED CONTENT
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Supporting Information. Copies of 1H and 13C NMR spectra, and chiral GC traces. This material is available free
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