Enantioselective Synthesis of 3,3-Difluoropyrrolidin-4-ol, a Valuable Building Block in Medicinal Chemistry

Article abstract of DOI:10.1021/acs.joc.6b00305

In this paper, we report for the first time two enantioselective routes to 4,4-difluoropyrrolidin-3-ol, a valuable building block in medicinal chemistry. In the first route, we took advantage of the C₂ symmetry of (3R,4R)-3,4-dihydroxypyrrolidine in which the desired chirality was derived from the chiral pool (l-(+)-tartaric acid). In the second route, we efficiently assembled the pyrrolidine ring in the presence of a gem-difluoro moiety to avoid using potentially hazardous deoxofluorinating reagents and subsequently introduced the chirality by a stereoselective iridium-diamine-catalyzed asymmetric transfer hydrogenation reaction.

Full text of DOI:10.1021/acs.joc.6b00305

Note
pubs.acs.org/joc
Enantioselective Synthesis of 3,3-Difluoropyrrolidin-4-ol, a Valuable
Building Block in Medicinal Chemistry
Chong Si,*,† Kevin R. Fales,† Alicia Torrado,‡ Kwame Frimpong,† Talbi Kaoudi,‡
Harold George Vandeveer,§ and F. George Njoroge†
†DCR&T, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States
‡DCR&T, Lilly Spain S.A., Avda de la Industria 30, Alcobendas Madrid, 28108, Spain
§AMRI, 26 Corporate Circle, Albany, New York 12203, United States
S
* Supporting Information
ABSTRACT: In this paper, we report for the first time two enantioselective routes to 4,4-difluoropyrrolidin-3-ol, a valuable
building block in medicinal chemistry. In the first route, we took advantage of the C2 symmetry of (3R,4R)-3,4-
dihydroxypyrrolidine in which the desired chirality was derived from the chiral pool (L-(+)-tartaric acid). In the second route, we
efficiently assembled the pyrrolidine ring in the presence of a gem-difluoro moiety to avoid using potentially hazardous
deoxofluorinating reagents and subsequently introduced the chirality by a stereoselective iridium−diamine-catalyzed asymmetric
transfer hydrogenation reaction.
luorine plays an increasingly important role in drug design
as a key building block in our SAR development. To the best of
our knowledge, there has been no enantioselective synthesis
reported for this class of compounds. Our initial route started
from the commercially available, C2-symmetric (R,R)-diol 2
which could be derived from L-(+)-tartaric acid.17
1−5
Fand development.
In particular, the introduction of a
gem-difluoro moiety into a molecule could modulate the pKa of
proximal functional groups,6 influence compound lipophilicity,7
alter molecular conformation,8 induce multiple interactions
with protein residues,9 and significantly improve metabolic
stability and pharmacokinetic properties.10 Several marketed
drugs (notable examples include gemcitabine, a nucleoside
analogue widely used as chemotherapy for cancer,11 maraviroc,
a CCR5 inhibitor for the treatment of HIV12), and numerous
drug candidates (e.g., PF-00734200, a DPP4 inhibitor that
progressed to phase 3 for the treatment of type 2 diabetes13)
have incorporated a gem-difluoro moiety in their molecular
structures (Figure 1). To enhance the general utility of this
functionality, there remains a need for efficient methods to
synthesize gem-difluorinated building blocks for medicinal
chemistry.14−16
Monoprotection of diol 2 was achieved by slow addition of
lithium diisopropylamide (LDA, 1.0 equiv) to a solution of diol
2 in 2-methyltetrahydrofuran, which led to immediate
precipitation of the monolithium alkoxide salt from the
solution, preventing further deprotonation. This lithium salt
was subsequently alkylated with benzyl bromide to provide the
monobenzylated product 3 in 50% yield. Oxidization of the free
alcohol with Dess−Martin periodinane yielded the correspond-
ing ketone,18 which underwent deoxo-fluorination with bis(2-
methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) to afford
difluoropyrrolidine 4 in 48% yield.19 Analysis of compound 4
with chiral HPLC indicated no detectable decrease in
enantiopurity. Finally, full deprotection by palladium hydroxide
catalyzed hydrogenation in the presence of hydrochloric acid
gave (R)-4,4-difluoropyrrolidin-3-ol hydrochloride 1 in quanti-
tative yield.
As part of a recent discovery program, we were interested in
enantioselective synthesis of (R)-4,4-difluoropyrrolidin-3-ol (1)
Although the route above in Scheme 1 was short and
efficient, it necessitated the use of a deoxo-fluorinating reagent
which is expensive and has safety concerns for large-scale
synthesis. Therefore, we decided to further develop an
Received: February 10, 2016
Figure 1. gem-Difluoro-containing pharmaceuticals.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b00305
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The Journal of Organic Chemistry
Note
Scheme 1. Synthesis of (R)-4,4-Difluoropyrrolidin-3-ol 1 from (R, R)-Diol 2
Scheme 2. Racemic Route to 4,4-Difluoropyrrolidin-3-ol
Scheme 3. Synthesis of (R)-4,4-Difluoropyrrolidin-3-ol 1 by Enantioselective Ketone Reduction
alternative route that circumvented these challenges. We
envisioned assembling the pyrrolidine ring from a readily
available gem-difluoride starting material and subsequently
introducing the chiral center by asymmetric ketone reduction.
In a model study, we developed a synthesis of racemic 4,4-
difluoropyrrolidin-3-ol as shown in Scheme 2. Starting from
readily available ethyl 2-bromo-2,2-difluoroacetates, indium-
mediated Reformatsky reaction20 with N-Boc-2-aminoacetalde-
hyde 5 provided alcohol 6, which was used crude after aqueous
workup. After deprotection with trifluoroacetic acid, the
pyrrolidinone ring was formed upon treatment with triethyl-
amine. Finally, pyrrolidinone 7 was reduced with sodium bis(2-
methoxyethoxy)aluminum hydride (Red-Al) to 4,4-difluoro-
pyrrolidin-3-ol 8 in 67% yield.
Based on this short racemic route (Scheme 2), we further
optimized the reaction conditions and developed an
enantioselective synthesis of 1 as shown in Scheme 3. Swern
oxidation of commercially available alcohol 9 provided
aldehyde 10 in 91% yield.21 It was found that an additional
benzyl protecting group on the amine not only added a
chromophore that was useful for purification of ensuring
intermediates but also helped to improve the stability of
aldehyde 10 (as compared to 5, which slowly decomposes at
room temperature) and led to higher yields in subsequent
steps. Next, Reformatsky reaction between 10 and ethyl
bromodifluoroacetate under Kumadaki’s rhodium-catalyzed
condition with 5 mol % of Wilkinson’s catalyst gave alcohol
11 in quantitative yield upon extractive isolation.22 N-Boc
removal of crude 11 with hydrochloric acid in 2-propanol and
lactam formation by stirring a biphasic mixture of crude amine
in ethyl acetate and saturated aqueous sodium carbonate
solution provided pyrrolidinone 12 in 88% yield. Subsequently,
alcohol 12 was oxidized to the corresponding ketone using
Ishihara’s procedure with Oxone in the presence of catalytic
amount of 2-iodoxybenzenesulfonic acid.23 This ketone was
found to exist in the hydrated form 13.14 In the key
enantioselective ketone reduction step, after examining many
possible conditions, we came to aqueous-phase asymmetric
transfer hydrogenation with sodium formate as the reductant24
and ultimately found Carreira’s iridium-catalyzed conditions
with (R,R)-TsDPEN (TsDPEN = N-(p-toluenesulfonyl)-1,2-
diphenylethylenediamine) as the ligand gave the desired (R)-
alcohol 14 in high yield (91%) and best enantioselectivity (98%
ee).25 Finally, pyrrolidinone 14 was reduced to amine by
refluxing with borane dimethyl sulfide complex in tetrahy-
drofuran, and subsequent hydrogenolytic cleavage of the benzyl
group catalyzed by palladium hydroxide in the presence of
hydrochloric acid provided (R)-4,4-difluoropyrrolidin-3-ol 1 in
excellent yields with no loss in chiral purity.
In summary, we have developed for the first time two
enantioselective routes to (R)-4,4-difluoropyrrolidin-3-ol, a
valuable building block in medicinal chemistry. Chirality was
introduced either from the chiral pool (L-(+)-tartaric acid) or
by using a highly stereoselective and high-yielding iridium
diamine ((R,R)-TsDPEN) catalyzed asymmetric transfer
hydrogenation. In the second route, we successfully avoided
using potentially hazardous deoxofluorinating reagents and
provided a practical route for future scale-up of this useful key
B
DOI: 10.1021/acs.joc.6b00305
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Note
min) ratio (99% e) with the other possible enantiomer determined by
intermediate. Given the (S,S)- stereoisomer of diol 2 and the
(S,S)-stereoisomer of ligand TsDPEN were also readily
available from commercial sources, these routes could be
applied to access the (S)-isomer of 4,4-difluoropyrrolidin-3-ol
as well.
chiral HPLC (Chiralpak AD-H, 4.6 × 100 mm; 100% EtOH, 1.0 mL/
1
min): H NMR (400 MHz, CDCl3) δ 7.40−7.27 (m, 10H), 5.14 (s,
2H), 4.80 (t, J = 10.9 Hz, 1H), 4.64 (t, J = 10.9 Hz, 1H), 4.01 (br. s.,
1H), 3.82 (dd, J = 18.2, 8.2 Hz, 1H), 3.80−3.74 (m, 2H), 3.70 (ddd, J
= 12.1, 5.5, 2.3 Hz, 1H), 3.60 (app t, J = 12.9 Hz, 1H); 19F NMR (377
MHz, CDCl3) −105.8 (dd, J = 245, 125 Hz), −122.1 (dd, J = 245, 214
Hz); 13C NMR (100 MHz, CDCl3) δ 154.5, 136.8, 136.2, 128.6, 128.5,
128.2, 128.1, 127.9, 122.1 (dd, J = 220, 40 Hz), 76.4−75.9 (m), 72.7,
67.4, 50.8−49.9 (m), 49.7 (d, J = 7.2 Hz); HRMS (ESI) calcd for
C19H19 F2NNaO3 [M + Na]+ = 370.1231, found 370.1228.
EXPERIMENTAL SECTION
■
All commercial reagents were used without further purification. All
solvents were reagent or HPLC grade. Flash chromatography was
carried out using an automated system with prepacked silica columns.
Yields refer to chromatographically and spectroscpically pure
compounds. 1H NMR, 13C NMR, and 19F NMR spectra were
recorded on 400/500 MHz spectrometers at ambient temperature (1H
NMR, 400/500 MHz; 19F NMR, 377/470 MHz; 13C NMR, 75/100
MHz). High-resolution mass spectra were recorded using a time-of-
flight mass spectrometer with an atmospheric pressure chemical
ionization source. Chiral analysis was performed using either HPLC or
supercritical fluid chromatography (SFC). The methods chosen were
based upon their ability to obtain baseline separation of the racemic
mixtures for the compounds of interest.
(R)-4,4-Difluoropyrrolidin-3-ol Hydrochloride (1). To a
solution of (4R)-4-(benzyloxy)-3,3-difluoropyrrolidine-1-carboxylate
4 (177 mg, 0.51 mmol) in ethanol (4.0 mL) was added palladium
hydroxide on carbon (35.4 mg, 0.051 mmol, 20 mass %). The vessel
was then closed and purged with hydrogen. The reaction was set under
hydrogen atmosphere (80 psi) and stirred at room temperature for 3
h. The reaction mixture was diluted with methanol and filtered. To the
filtrate was added 1 N HCl in methanol. Solvents were removed under
reduced pressure. The crude was triturated with 2-propanol/hexane
(1:1) to provide (3R)-4,4-difluoropyrrolidin-3-ol hydrochloride 1 (81
20
mg, 0.51 mmol, in quantitative yield): [α]D = −12.3 (c 1.0, H2O);
Benzyl (3R,4R)-3-(Benzyloxy)-4-hydroxypyrrolidine-1-
carboxylate(3). To a solution of benzyl (3R,4R)-3,4-dihydroxypyrro-
lidine-1-carboxylate (1.00 g, 4.22 mmol) in 2-ethyltetrahydrofuran (20
mL) was added 2.0 M lithium diisopropylamide solution in
tetrahydrofuran (2.11 mL, 4.22 mmol) dropwise. As the base was
added, the lithium alkoxide salt precipitated. Once addition was
completed, the reaction mixture was concentrated to dryness. The
residue was dissolved in dimethylformamide (2 mL), and benzyl
bromide (1.00 mL, 8.43 mmol) was added. The reaction mixture was
stirred at room temperature for 18 h. The crude material was purified
by flash chromatography (25−100% ethyl acetate in hexanes) to afford
benzyl (3R,4R)-3-(benzyloxy)-4-hydroxypyrrolidine-1-carboxylate 3
1
mp 180−181 °C; H NMR (400 MHz, DMSO-d6) δ 10.21 (2H, s),
6.60 (1H, s), 4.31 (1H, m), 3.7−3.5 (2H, m), 3.5−3.4 (1H, m), 3.21
(1H, dt, J = 12.5, 2.9 Hz); 19F NMR (377 MHz, DMSO-d6) −106.3
(d, J = 240 Hz), −120.58 (d, J = 238 Hz); 13C NMR (100 MHz,
DMSO-d6) δ 126.2 (dd, J = 258, 246 Hz), 69.5 (dd, J = 30.8, 19.8 Hz),
49.5, 47.2 (t, J = 32.8 Hz); HRMS (ESI) calcd for C4H8F2NO [M +
H]+ = 124.0574, found 124.0571.
3,3-Difluoro-4-hydroxypyrrolidin-2-one (7). A mixture of tert-
butyl N-(2-oxoethyl)carbamate (53.0 g, 333 mmol), indium powder
(40.1 g, 350 mmol, 1.05 equiv), and ethyl bromodifluoroacetate (45.8
mL, 350 mmol, 1.05 equiv) in THF (800 mL) was heated to 55 °C for
16 h. After being cooled to ambient temperature, the mixture was
quenched by the addition of satd aq NH4Cl solution. Most solvents
were removed under reduced pressure. The residue was diluted with 1
N aq HCl solution and extracted three times with ethyl acetate. The
combined organic layers were washed with water and brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure to afford
ethyl 4-(tert-butoxycarbonylamino)-2,2-difluoro-3-hydroxybutanoate 6
(70.0 g, 333 mmol) as a dark amber oil which was used without further
purification.
20
(690 mg, 50% yield) as off-white solid: [α]D = +2.67 (c 0.6,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.41−7.27 (m, 10H), 5.12 (s,
2H), 4.56 (dd, J = 13.1, 12.1 Hz, 2H), 4.29−4.33 (m, 1H), 3.92 (s,
1H), 4.56 (app td, J = 11.9, 4.0 Hz, 2H), 3.64−3.40 (m, 2H), 1.88 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 155.1, 137.5, 136.7, 128.5,
128.4, 128.0, 127.9, 127.9, 127.7, 77.2, 71.4, 66.9, 52.1, 49.2; HRMS
(ESI) calcd for C19H22NO4 [M + H]+ = 328.1549, found 328.1556.
Benzyl (R)-3-(Benzyloxy)-4-oxopyrrolidine-1-carboxylate
(3a). To a solution of benzyl (3R,4R)-3-(benzyloxy)-4-hydroxypyrro-
lidine-1-carboxylate (350 mg, 1.07 mmol) in dichloromethane (5 mL)
was added Dess−Martin periodinane (544 mg, 1.28 mmol). After 3 h,
the reaction mixture was diluted with ethyl acetate, washed with a
1:1:1 mixture of saturated aqueous Na2S2O3 solution, saturated
aqueous NaHCO3 solution, and brine, dried over Na2SO4, filtered, and
concentrated to give benzyl (3R)-3-(benzyloxy)-4-oxo-pyrrolidine-1-
carboxylate (348 mg, 100%) as an off-white solid: 1H NMR (400
MHz, CDCl3) δ 7.44−7.27 (m, 10H), 5.16 (s, 2H), 4.84 (d, J = 11.8
Hz, 1H), 4.67 (d, J = 11.8 Hz, 1H), 4.19−4.07 (m, 1H), 4.08 (t, J = 8.2
Hz, 1H), 3.95 (d, J = 18.7 Hz, 1H), 3.84 (d, J = 18.7 Hz, 1H), 3.57−
3.46 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 208.2, 154.8, 136.6,
136.1, 128.6, 128.6, 128.3, 128.2, 128.1, 77.3, 72.6, 67.5, 51.2, 48.3;
HRMS (ESI) calcd for C19H20NO4 [M + H]+ = 326.1392, found
326.1387.
The crude ethyl 4-(tert-butoxycarbonylamino)-2,2-difluoro-3-hy-
droxybutanoate 6 (70.0 g, 333 mmol) was dissolved in 200 mL of
DCM. Trifluoroacetic acid (126 mL, 1.66 mol, 5.00 equiv) was added.
The mixture was stirred at ambient temperature for 2 h and
concentrated under reduced pressure. The residue was dissolved in
acetonitrile and concentrated to dryness. The crude intermediate (4-
ethoxy-3,3-difluoro-2-hydroxy-4-oxobutyl)ammonium;2,2,2-trifluoroa-
cetate was dissolved in 350 mL of acetonitrile. Triethylamine (234 mL,
1.66 mol, 5.00 equiv) was added. The mixture was stirred at ambient
temperature for 16 h and then concentrated under reduced pressure.
The residue was purified by flash chromatography (40% acetone in
hexanes) to give 3,3-difluoro-4-hydroxypyrrolidin-2-one 7 (16.4 g, 120
1
mmol, 36% over three steps) as a yellow solid: mp 136−138 °C; H
NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 6.16 (d, J = 5.8 Hz, 1H),
4.33 (qd, J = 11.7, 5.9 Hz, 1H), 3.54−3.50 (m, 1H), 3.00 (dd, J = 10.0,
5.00 Hz, 1H); 19F NMR (377 MHz, DMSO-d6) δ −119.0 − −119.7
(d, J = 264.3 Hz), −125.5 − −126.2 (d, J = 264.3 Hz); 13C NMR (100
MHz, DMSO-d6) δ 164.0 (t, J = 59.4 Hz), 113.5 (t, J = 506.2 Hz),
67.8 (q, J = 44.8 Hz), 44.5 (d, J = 8.1 Hz); HRMS (ESI) calcd for
C4H5F2NNaO2 [M + Na]+ = 160.0186, found 160.0183.
Benzyl (R)-4-(Benzyloxy)-3,3-difluoropyrrolidine-1-carboxy-
late (4). To a solution of crude benzyl (3R)-3-(benzyloxy)-4-
oxopyrrolidine-1-carboxylate (348 mg, 1.07 mmol) in dichloro-
methane (20 mL) was added (bis(2-methoxyethyl)amino)sulfur
trifluoride (480 mg, 2.17 mmol). After 18 h, the reaction mixture
was quenched by cooling to 0 °C and slowly pouring into saturated
aqueous NaHCO3 solution, allowing for CO2 evolution. The layers
were separated; aqueous layer was extracted twice with dichloro-
methane. The organic layers were combined, washed with brine, dried
over Na2SO4, filtered, and concentrated. The crude material was
purified by flash chromatography (20% MBTE in hexanes) to afford
benzyl (4R)-4-(benzyloxy)-3,3-difluoropyrrolidine-1-carboxylate 4
4,4-Difluoropyrrolidin-3-ol (8). 3,3-Difluoro-4-hydroxypyrroli-
din-2-one 7 (0.700 g, 5.11 mmol) was dissolved in THF (20 mL).
The mixture was purged with N2 and cooled to 0 °C. Red-Al (60 mass
%) in toluene (8.30 mL, 25.5 mmol, 5.00 equiv) was added dropwise.
The mixture was stirred for 16 h while warming to ambient
temperature. The mixture was cooled back to 0 °C and carefully
quenched with solid Na2SO4·10H2O until gas evolution ceased.
Additional solid Na2SO4·10H2O was added, and the mixture was
20
(177 mg, 48% yield): mp 78.0−78.5 °C; [α]D = +6.52 (c 0.5,
CHCl3). Chiral analysis indicated a 99.5 (tR = 4.15 min): 0.5 (tR = 3.78
C
DOI: 10.1021/acs.joc.6b00305
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Note
stirred for 1 h and filtered over a pad of Celite. The cake was diluted
with THF, stirred for 20 min, and filtered. This was repeated 2×. The
combined filtrates were concentrated under reduced pressure. The
crude material was purified by flash chromatography (0−10%
methanol in dichloromethane) to afford 4,4-difluoropyrrolidin-3-ol 8
(0.420 g, 3.41 mmol, 67% yield) as light cream solid: mp 85.8−86.2
MHz) δ − 113.19 (d, J = 261.79 Hz), −125.08 (d, J = 262.26 Hz); 13
C
NMR (CDCl3, 75 MHz) δ 162.1 (t, J = 32.5 Hz), 157.4, 136.3, 127.7,
126.6, 126.3, 113.0 (t, J = 260.5 Hz), 80.6, 70.8 (t, J = 27.8 Hz), 62.0,
51.5, 46.4, 27.3, 12.9; HRMS (m/z) calcd for C18H25F2NNaO5 [M +
Na]+ = 396.1598, found 396.1603.
1-Benzyl-3,3-difluoro-4-hydroxypyrrolidin-2-one (12). Crude
ethyl 4-[benzyl(tert-butoxycarbonyl)amino]-2,2-difluoro-3-hydroxybu-
tanoate (35.2 g, 94.3 mmol) was dissolved in 2-propanol (53 mL) and
was added to a solution of hydrochloric acid (176 mL, 4.99 M in 2-
propanol) at room temperature. The resulting solution was stirred for
1 h at room temperature. The solvents were then evaporated to
dryness. The resulting solid was cooled to 0 °C and suspended in ethyl
acetate (300 mL). Saturated aq Na2CO3 (200 mL) was added, and the
resulting biphasic mixture was vigorously stirred (keeping the pH > 9)
for 40 min at 0 °C. The two phases were separated, and the aqueous
phase was extracted twice with ethyl acetate. The combined organic
phases were washed with brine, dried over Na2SO4, filtered, and
evaporated to dryness to give the desired product together with
triphenylphosphine oxide. The crude was dissolved in ethyl acetate
and passed through a silica gel pad (eluent: 100% ethyl acetate) to
obtain 1-benzyl-3,3-difluoro-4-hydroxy-pyrrolidin-2-one (18.6 g, 82
mmol, 88%) as a light brown solid: 1H NMR (DMSO-d6, 400 MHz) δ
7.39−7.30 (3H, m), 7.23 (2H, d, J = 7.2 Hz), 6.22 (1H, d, J = 5.7 Hz),
4.57 (1H, d, J = 14.8 Hz), 4.38 (1H, d, J = 14.8 Hz), 4.43−4.33 (1H,
m), 3.56 (1H, dd, J = 10.4, 6.7 Hz), 3.04 (1H, dd, J = 10.4, 4.4 Hz);
19F NMR (CDCl3, 470 MHz) δ −116.61 (d, J = 274.0 Hz), −126.95
(d, J = 273.5 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 161.4 (t, J = 30.4
Hz), 134.6, 128.2, 127.25, 127.21, 115.37 (dd, J = 254.9, 250.9 Hz),
65.5 (dd, J = 27.3, 17.5 Hz), 48.6 (d, J = 6.0 Hz), 45.6; HRMS (m/z)
calcd for C11H11F2NNaO2 [M + Na]+ = 250.0656, found 250.0648.
1-Benzyl-3,3-difluoro-4,4-dihydroxypyrrolidine-2-one (13).
To a solution of 1-benzyl-3,3-difluoro-4-hydroxypyrrolidin-2-one
(1.00 g, 4.40 mmol) in acetonitrile (20 mL) were added potassium
2-iodo-5-methylbenzenesulfonate (75 mg, 0.20 mmol) and potassium
peroxymonosulfate (2.65 g, 8.80 mmol). The resulting mixture was
heated to reflux at 90 °C for 16 h. The reaction was diluted with ethyl
acetate, and the precipitated solid was filtered through a Celite pad and
washed with ethyl acetate. The filtrate was passed to a separatory
funnel and washed with satd aq Na2S2O3 solution, satd aq NaHCO3
solution, and brine. The organic phase was separated, dried over
Na2SO4, and filtered, and the solvents were removed under reduced
pressure. The crude was purified by flash chromatography (0 to 60%
hexanes in acetone) to afford 1-benzyl-3,3-difluoro-4,4-dihydroxypyr-
rolidine-2-one 13 (740 mg, 3.30 mmol, 75%) as a white solid: mp
128−129 °C; 1H NMR (DMSO-d6, 500 MHz) δ 7.43−7.30 (3H, m),
7.23 (2H, d, J = 7.3 Hz), 7.17 (2H, s), 4.49 (2H, s), 3.29 (2H, s); 19F
NMR (DMSO-d6, 470 MHz) δ −126.9 (s); 13C NMR (DMSO-d6, 75
MHz) δ 161.8 (t, J = 29.7 Hz), 134.6, 128.2, 127.14, 127.10, 112.2 (t, J
= 256.8 Hz), 91.0 (t, J = 20.8 Hz), 54.4, 45.2; HRMS (m/z) calcd for
C11H12F2NO3, [M + H]+ = 244.0785, found 244.0786.
(4R)-1-Benzyl-3,3-difluoro-4-hydroxypyrrolidin-2-one (14).
A mixture of (1R,2R)-(−)-N-(4-toluenesulfonyl)-1,2-diphenylethyle-
n e d i a m i n e ( 0 . 2 0 g , 0 . 5 0 m m o l ) a n d d i c h l o r o -
(pentanemethylcyclopentadienyl)iridium(III) dimer (0.22 g, 0.30
mmol) in ethyl acetate (15 mL) and water (60 mL) was vigorously
stirred at 40 °C under nitrogen for 30 min. The resulting bright orange
mixture was cooled to room temperature. Sodium formate (18.0 g, 270
mmol) was added, and the reaction mixture turned black. After 10
min, the reaction mixture turned yellow-orange. 1-Benzyl-3,3-difluoro-
4,4-dihydroxypyrrolidine-2-one (1.50 g, 6.70 mmol) was then added in
one portion. The mixture turned purple and then back to yellow-
orange again. After 30 min, the reaction mixture was diluted with ethyl
acetate and water. The organic layer was separated, and the aqueous
layer was extracted with additional ethyl acetate. The combined
organic layers were washed with water, dried over Na2SO4, and
filtered, and the solvents were removed under reduced pressure. The
residue was purified by flash chromatography (0−60% hexanes in
acetone to afford (4R)-1-benzyl-3,3-difluoro-4-hydroxypyrrolidin-2-
one 14 (1.40 g, 6.10 mmol, 91%) as a light brown solid in a 99 (tR =
0.86 min): 1 (tR = 0.78 min) ratio with the other possible enantiomer
1
°C; H NMR (400 MHz, CDCl3) δ 4.14−4.11 (m, 1H), 3.36−3.16
(m, 3H), 3.00 (d, J = 12.5 Hz, 1H), 2.57−2.55 (bs, 2H); 19F NMR
(377 MHz, CDCl3) δ −104.6 − −105.2 (d, J = 239.8 Hz), −121.0 to
−121.6 (d, J = 239.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 126.9
(t, J = 508.4 Hz), 72.5 (dd, J = 50.6, 30.1 Hz), 52.7, 52.4 (d, J = 25.0
Hz); HRMS (ESI) calcd for C4H8F2NO [M + H]+ = 124.05740, found
124.05739.
tert-Butyl N-Benzyl-N-(2-oxoethyl)carbamate (10). To a
solution of dimethyl sulfoxide (21.0 mL, 298.4 mmol) in dichloro-
methane (375 mL) at −78 °C was added dropwise 2 M oxalyl chloride
solution in dichloromethane (74.6 mL, 149.2 mmol). The resulting
solution was stirred at −78 °C for 20 min. To this mixture was then
added a solution of tert-butyl N-benzyl-N-(2-hydroxyethyl)carbamate
(25.0 g, 99.5 mmol) in dichloromethane (125 mL). The resulting
solution was stirred at −78 °C for 2 h after the addition was
completed. Then triethylamine (125 mL, 895.3 mmol) was added.
Once the addition was completed, the reaction was allowed to slowly
warm to 0 °C and allowed to stir at this temperature for 30 min. The
reaction was quenched by addition of a 10% aq solution of citric acid.
The resulting mixture was stirred for 15 min, and then the two phases
were separated. The aqueous phase was extracted with additional
dichloromethane. The combined organic phases were washed with
10% aq solution of citric acid, water, satd aq Na2CO3 solution, and
brine, dried over Na2SO4, and filtered, and the solvents were removed
under reduced pressure. The crude was absorbed on silica gel and
purified by flash chromatography (0−50% ethyl acetate in hexanes).
The fractions containing desired product were collected and
evaporated to dryness to obtain tert-butyl N-benzyl-N-(2-oxoethyl)-
carbamate 10 (23.6 g, 90.9 mmol, 91%) as a light yellow oil. The
product showed two sets of peaks as equilibrium of rotamers: 1H
NMR (CDCl3, 400 MHz): δ 9.49 and 9.42 (2 s, 1 H), 7.40−7.16 (m,
5H), 4.55 (s, 1H), 4.50 (s, 1H), 3.93 (s, 1H), 3.78 (s, 1H), 1.49 and
1.47 (2 s, 9H); 13C NMR (CDCl3, 75 MHz): δ 197.8, 154.8 and 154.4,
136.3 and 136.1, 127.7, 127.1, 126.7, 126.5, 80.0, 55.4, 51.0 and 50.5,
27.3, and 27.2; HRMS (m/z) calcd for C14H19NNaO3, [M + Na]+ =
272.1263, found 272.1258.
Ethyl 4-[Benzyl(tert-butoxycarbonyl)amino]-2,2-difluoro-3-
hydroxy-butanoate (11). To a suspension of chlorotris-
(triphenylphosphine)rhodium(I) (4.50 g, 5.00 mmol) in acetonitrile
(353 mL) were added tert-butyl N-benzyl-N-(2-oxoethyl)carbamate
(25 g, 100.3 mmol) and ethyl 2-bromo-2,2-difluoroacetate (48.3 mL,
401.1 mmol). The resulting mixture was cooled to −30 °C, and
diethylzinc (377 mL, 401 mmol, 1.0 M in hexane) was added to the
mixture over a period of 45 min (no exotherm was observed). The
reaction temperature was maintained between −30 and −20 °C during
the addition. The reaction was then allowed to slowly warm from −20
to 0 °C and was kept at 0 °C for 30 min. The reaction was quenched
(at 0 °C) by addition of a 20% aq citric acid solution and diluted with
ethyl acetate. The resulting biphasic solution was stirred for 30 min.
The two phases were separated, and the aqueous phase was extracted
with additional ethyl acetate. The combined organic phases were
washed with 20% aq citric acid solution, 2 N aq NaOH solution, satd
NH4Cl, and brine, dried over Na2SO4, and filtered, and the solvents
were removed under reduced pressure. The crude was dried under
high vacuum to afford crude ethyl 4-[benzyl(tert-butoxycarbonyl)-
amino]-2,2-difluoro-3-hydroxy-butanoate 11 (37.4 g, 100 mmol, in
quantitative yield) as a brown oil. This crude was used without further
purification on the next step. A small amount of the sample was
purified by flash chromatography (0−30% ethyl acetate in hexanes) to
1
obtain pure product (a colorless oil) for analytical data: H NMR
(CDCl3, 500 MHz) δ 7.43−7.21 (5H, m), 4.86 (1H, broad s), 4.56
(1H, d, J = 15 Hz), 4.42 (1H, d, J = 16.5 Hz), 4.36 (2H, q, J = 7
Hz),4.26−4.15 (1H, m), 3.83 (1H, dd, J = 15, 9.5 Hz), 3.33 (1H, d, J =
15 Hz), 1.49 (9H, s), 1.37 (3H, t, J = 7 Hz); 19F NMR (CDCl3, 470
D
DOI: 10.1021/acs.joc.6b00305
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(98% ee) determined by chiral SFC (Chiralpak ID, 4.6 × 100 mm, 5
μm; 15−55% iPrOH in CO2, 4 mL/min): [α]D = +10.7 (c 1.0,
ACKNOWLEDGMENTS
■
20
We are grateful to Thomas Perun and Eric Seest for help with
chiral analysis, Christopher Reutter for his help with HRMS,
and Aida Fernandez for her help with optical rotation.
EtOH); mp 71.3−71.6 °C; 1H NMR (CDCl3, 500 MHz) δ 7.40−7.35
(3H, m), 7.26−7.25 (2H, m), 4.56 (2H, s), 4.42−4.37 (1H, m), 3.55
(1H, dd, J = 10.7, 6.1 Hz), 3.18 (1H, ddd, J = 11, 3.5, 1.5 Hz), 2.68−
2.61 (1H, broad s); 19F NMR (CDCl3, 470 MHz) δ − 116.64 (d, J =
273.5 Hz), −127.04 (d, J = 273.5 Hz);13C NMR (CDCl3, 75 MHz) δ
161.5 (t, J = 30.7 Hz), 133.0, 128.0, 127.3, 127.2, 114.2 (t, J = 256.7
Hz), 66.2 (dd, J = 29.3, 18.7 Hz), 48.25 (d, J = 4.1 Hz), 46.2; HRMS
(m/z) [M + H]+ calcd for C11H11F2NNaO2 250.0656, found
250.0650.
REFERENCES
■
(1) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;
Meanwell, N. A. J. Med. Chem. 2015, 58, 8315.
(2) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
(3) Isanbor, C.; O’Hagan, D. J. Fluorine Chem. 2006, 127, 303.
(4) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(5) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320.
(6) Morgenthaler, M.; Schweizer, E.; Hoffmann-Roder, A.; Benini, F.;
Martin, R. E.; Jaeschke, G.; Wagner, B.; Fischer, H.; Bendels, S.;
Zimmerli, D.; Schneider, J.; Diederich, F.; Kansy, M.; Muller, K.
ChemMedChem 2007, 2, 1100.
(3R)-1-Benzyl-4,4-difluoropyrrolidin-3-ol (14a). To a solution
of (4R)-1-benzyl-3,3-difluoro-4-hydroxypyrrolidin-2-one 14 (1.00 g,
4.40 mmol) in tetrahydrofuran (10 mL) was added borane dimethyl
sulfide complex (1.35 mL, 13.2 mmol) and the mixture stirred at room
temperature for 20 min. The reaction mixture was then heated. After 3
h, the reaction was quenched by slow addition of ethanol (10 mL,
CAUTION: gas generation) at 0 °C. The mixture was then refluxed
overnight. The solvents were removed under reduced pressure. The
crude was dissolved in 1 M hydrogen chloride methanol solution (20
mL) and 20% weight/weight activated carbon. The slurry was stirred
for 1 h at room temperature and filtered over a membrane of
polypropane (0.45 μm). The active carbon was then washed with
MeOH. The solvents were removed under reduced pressure, and the
solid was further dried under high vacuum to give (3R)-1-benzyl-4,4-
difluoropyrrolidin-3-ol hydrochloride (920 mg, 4.31 mmol, 98% yield)
as a white solid. A fraction of the HCl salt was liberated to generate the
̈
̈
́
(7) Truong, A. P.; Toth, G.; Probst, G. D.; Sealy, J. M.; Bowers, S.;
Wone, D. W. G.; Dressen, D.; Hom, R. K.; Konradi, A. W.; Sham, H.
L.; Wu, J.; Peterson, B. T.; Ruslim, L.; Bova, M. P.; Kholodenko, D.;
Motter, R. N.; Bard, F.; Santiago, P.; Ni, H.; Chian, D.; Soriano, F.;
Cole, T.; Brigham, E. F.; Wong, K.; Zmolek, W.; Goldbach, E.;
Samant, B.; Chen, L.; Zhang, H.; Nakamura, D. F.; Quinn, K. P.;
Yednock, T. A.; Sauer, J.-M. Bioorg. Med. Chem. Lett. 2010, 20, 6231.
(8) Jansen, K.; Heirbaut, L.; Verkerk, R.; Cheng, J. D.; Joossens, J.;
Cos, P.; Maes, L.; Lambeir, A. M.; De Meester, I.; Augustyns, K.; Van
der Veken, P. J. Med. Chem. 2014, 57, 3053.
1
analytical data: mp 69.8−71.1 °C; H NMR (CDCl3, 500 MHz) δ
(9) Dubowchik, G. M.; Vrudhula, V. M.; Dasgupta, B.; Ditta, J.;
Chen, T.; Sheriff, S.; Sipman, K.; Witmer, M.; Tredup, J.; Vyas, D. M.;
Verdoorn, T. A.; Bollini, S.; Vinitsky, A. Org. Lett. 2001, 3, 3987.
(10) Kerekes, A. D.; Esposite, S. J.; Doll, R. J.; Tagat, J. R.; Yu, T.;
Xiao, Y.; Zhang, Y.; Prelusky, D. B.; Tevar, S.; Gray, K.; Terracina, G.
A.; Lee, S.; Jones, J.; Liu, M.; Basso, A. D.; Smith, E. B. J. Med. Chem.
2011, 54, 201.
(11) Hertel, L. W.; Boder, G. B.; Kroin, J. S.; Rinzel, S. M.; Poore, G.
A.; Todd, G. C.; Grindey, G. B. Cancer Res. 1990, 50, 4417.
(12) Dorr, P.; Westby, M.; Dobbs, S.; Griffin, P.; Irvine, B.;
Macartney, M.; Mori, J.; Rickett, G.; Smith-Burchnell, C.; Napier, C.;
Webster, R.; Armour, D.; Price, D.; Stammen, B.; Wood, A.; Perros,
M. Antimicrob. Agents Chemother. 2005, 49, 4721.
(13) Sharma, R.; Sun, H.; Piotrowski, D. W.; Ryder, T. F.; Doran, S.
D.; Dai, H.; Prakash, C. Drug Metab. Dispos. 2012, 40, 2143.
(14) Surmont, R.; Verniest, G.; Thuring, J. W.; Macdonald, G.;
Deroose, F.; De Kimpe, N. J. Org. Chem. 2010, 75, 929.
(15) Wei, L.; Makowski, T. M.; Rutherford, J. L. J. Fluorine Chem.
2012, 135, 354.
(16) McAlpine, I.; Tran-Dube, M.; Wang, F.; Scales, S.; Matthews, J.;
Collins, M. R.; Nair, S. K.; Nguyen, M.; Bian, J.; Alsina, L. M.; Sun, J.;
Zhong, J.; Warmus, J. S.; O’Neill, B. T. J. Org. Chem. 2015, 80, 7266.
(17) Kang, Y. K.; Shin, K. J.; Yoo, K. H.; Seo, K. J.; Park, S. Y.; Kim,
D. J.; Park, S. W. Bioorg. Med. Chem. Lett. 1999, 9, 2385.
(18) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(19) Singh, R. P.; Shreeve, J. n. M. Synthesis 2002, 2002, 2561.
(20) Poisson, T.; Belhomme, M. C.; Pannecoucke, X. J. Org. Chem.
2012, 77, 9277.
7.37−7.31 (5H, m), 4.24−4.22 (1H, m), 3.67 (2H,ABq, ΔδAB = 0.03,
JAB= 12.8 Hz), 3.09 (1H, dd, J = 10.5, 6 Hz), 3.04−2.91 (2H, m), 2.64
(1H, ddd, J = 10.1, 4.8, 2.5 Hz), 2.30 (1H, d, J = 5.2 Hz); 19F NMR
(CDCl3, 470 MHz) δ − 100.53 (d, J = 236.4 Hz), −113.53 (d, J =
236.4 Hz); 13C NMR (CDCl3, 75 MHz): δ 137.1, 128.9, 128.6, 127.6,
126.0 (t, J = 254.7 Hz), 73.35 (dd, J = 31.6, 18.9 Hz), 59.7, 59.6 (t, J =
28.4 Hz), 59.4 (d, J = 4.6 Hz); HRMS (m/z) [M + H]+ calcd for
C11H14F2NO 214.1043, found 214.1041.
(3R)-4,4-Difluoropyrrolidin-3-ol Hydrochloride (1). To a
solution of (3R)-1-benzyl-4,4-difluoropyrrolidin-3-ol hydrochloride
(1100 mg, 4.40 mmol) in ethanol (11 mL) was added palladium
hydroxide on carbon (310 mg, 0.44 mmol, 20 mass %). The vessel was
then closed and purged with hydrogen. The reaction was set under
hydrogen atmosphere (80 psi) and allowed to stir at room
temperature for 3 h. The reaction mixture was diluted with methanol
and filtered, and the solvent was removed under reduced pressure. The
crude was triturated with 2-propanol/hexane (1:1), filtered, dried, and
collected. The solid was further dried under high vacuum overnight to
obtain (3R)-4,4-difluoropyrrolidin-3-ol hydrochloride 1 (703 mg, 4.38
20
mmol, 99%): [α]D = −12.0 (c 1.0, H2O). All of the other analytical
data were identical to previous analyses.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
(21) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(22) Sato, K.; Tarui, A.; Kita, T.; Ishida, Y.; Tamura, H.; Omote, M.;
Ando, A.; Kumadaki, I. Tetrahedron Lett. 2004, 45, 5735.
(23) Uyanik, M.; Akakura, M.; Ishihara, K. J. Am. Chem. Soc. 2009,
131, 251.
ACS Publications website at DOI: 10.1021/acs.joc.6b00305.
1H, 13C, and 19F NMR spectra for reported compounds
and HPLC chromatograms for compounds 4 and 14
(PDF)
(24) Wu, X.; Xiao, J. Chem. Commun. 2007, 2449.
(25) Vazquez-Villa, H.; Reber, S.; Ariger, M. A.; Carreira, E. M.
Angew. Chem., Int. Ed. 2011, 50, 8979.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: +1-317-433-5853. E-mail: si_chong@lilly.com
Notes
The authors declare no competing financial interest.
E
DOI: 10.1021/acs.joc.6b00305
J. Org. Chem. XXXX, XXX, XXX−XXX