Fluorination-free synthesis of a 4,4-difluoro-3,3-dimethylproline derivative

Article abstract of DOI:10.1021/jo060057p

A Claisen rearrangement/iodolactamization sequence starting from commercially available trifluoroacetaldehyde methyl hemiacetal, followed by a classical chemical resolution, provided enantiomerically pure 4,4-difluoro-3,3-dimethylproline (S)-1. No hazardo

Full text of DOI:10.1021/jo060057p

Fluorination-Free Synthesis of a 4,4-Difluoro-3,3-Dimethylproline
Derivative
Lijian Chen,* Young Mi Kim, David J. Kucera, Katheryn E. Harrison, Sogole Bahmanyar,
Jill M. Scott, and Daniel Yazbeck
Chemical Research and DeVelopment, La Jolla Laboratories, Pfizer, Inc., 10578 Science Center DriVe,
San Diego, California 92121-1111
lijianc@amgen.com
ReceiVed January 10, 2006
A Claisen rearrangement/iodolactamization sequence starting from commercially available trifluoroacet-
aldehyde methyl hemiacetal, followed by a classical chemical resolution, provided enantiomerically pure
4,4-difluoro-3,3-dimethylproline (S)-1. No hazardous fluorination reagents were used, and the overall
yield over 12 steps was greater than 28%.
Introduction
Compound (S)-1 is a key building block for a number of
second-generation HIV protease inhibitors, such as 2 and 3.1
The original synthesis involved ketone fluorination with DAST
or Deoxo-Fluor,2 which are hazardous and expensive, and
fluorination yields were less than 50%. To accommodate large-
scale production, a fluorination-free synthesis was sought.
Results and Discussion
The synthetic strategy was to form pyrrolidinone 7 from
acyclic amide 6 via iodolactamization (Scheme 1), followed by
substitution, protecting group exchange, and oxidation-state
adjustment to give (()-1. A Claisen rearrangement was expected
to establish the adjacent gem difluoro and dimethyl quaternary
carbons of acid 5.
Claisen reactions is well studied and high yielding3 (Scheme
2), a similar reaction sequence with acetate 4 under identical
conditions resulted only in fragmentation to difluoroacetic acid
and isoprene (Scheme 3). Experiments showed that ester 4 was
unstable at high temperatures under acidic or basic conditions
and liberated isoprene by 1,4-elimination. Traditional zinc
activation techniques such as iodine or ethylene dibromide
induction, or acid washing, failed to facilitate the conversion
of 4 to 5.
Although formation of 2,2-difluoropent-4-enoic acid from
allyl chlorodifluoroacetate via sequential Reformatskii and
* Current address: Chemical Process Research and Development, Amgen,
One Amgen Center Drive, Thousand Oaks, CA 91320. Tel: 805-313-5212.
Fax: 805-375-4531.
(1) (a) Kucera, D. J.; Scott, R. W. U.S. Patent Appl. 20040204591, 2004.
(b) Kucera, D. J.; Saeed, N. L.; Scott, R. W. PCT Int. Appl. WO2005054187,
2005.
(2) Canan-Koch, S. S.; Alexander, T. N.; Barvian, M.; Bolton, G.; Boyer,
F. E.; Burke, B. J.; Holler, T.; Jewell, T. M.; Prasad, J. V.; Kucera, D. J.;
Linton, M. A.; Machak, J.; Mitchell, L. J.; Murphy, S. T.; Reich, S. H.;
Skalitzky, D. J.; Tatlock, J. H.; Varney, M. D.; Virgil, S. C.; Webber, S.
E.; Worland, S. T.; Melnick, M. PCT Int. Appl. WO 2002100844, 2002.
(3) (a) Greuter, H.; Lang, R. W.; Romann, A. J. Tetrahedron Lett. 1988,
29, 3291. (b) Tang, W.; Borel, A. G.; Fujimiya, T. ; Abbott, F. S. Chem.
Res. Toxicol. 1995, 8, 671.
10.1021/jo060057p CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/20/2006
5468
J. Org. Chem. 2006, 71, 5468-5473

Synthesis of a 4,4-Difluoro-3,3-Dimethylproline DeriVatiVe
SCHEME 1
SCHEME 6
SCHEME 2
SCHEME 3
SCHEME 7 a
SCHEME 4 a
a Key: (a) powdered K2CO3, n-Bu4NBr, THF, 23 °C; (b) n-BuLi, THF,
<-60 °C; (c) BnNH2, <-60 °C; (d) warm to 0 °C, 80% from trifluoro-
acetaldehyde methyl hemiacetal.
or an epoxidation-cyclization sequence (Scheme 6). But under
the strongly basic dehydrofluorination conditions, the newly
formed difluorovinyl ether presumably underwent further depro-
tonation to generate highly reactive vinyllithium species 9, which
likely decomposed under the reaction conditions. To avoid
vinyllithium formation, acetal 10, whose corresponding vinyl
ether has no acidic vinyl proton, was investigated (Scheme 7).
Commercially available trifluoroacetaldehyde methyl hemiacetal
was reacted with 3,3-dimethylallyl bromide to give acetal 10
in nearly quantitative yield. Compound 10 was treated with
n-BuLi to generate vinyl ether 11, which underwent a Claisen
rearrangement upon warming to about 0 °C. Theoretically, only
1 equiv of n-BuLi was needed for this transformation, but in
practice, 2 equiv of n-BuLi was required to complete the
conversion to 8. The need for an additional 1 equiv of n-BuLi
was possibly due to formation of an insoluble n-BuLi‚LiF
complex. Benzylamine was then added to the basic mixture to
form amide 6, which was thus formed directly without isolation
of ester 8.
a Key: (a) (COCl)2; (b) BnNH2.
SCHEME 5 a
a Key: (a) (i) Zn, TMSCl, DMI, 25 °C, (ii) 100 °C; (b) H2O, 68% from
4; (c) H2SO4, CH(OMe)3, 88%; (d) BnNH2, DMAP, EtOAc, 96%.
Britton reported mild conditions to form 2,2-difluoroketene
silyl acetals from chlorodifluoroacetates in 1,3-dimethylimida-
zolidin-2-one (DMI) solvent.4 When these conditions were tested
on substrate 4, a >50% yield of crude 5 was obtained. Acid 5
was converted to the corresponding acid chloride and was then
treated with benzylamine. A large amount of N-benzyldifluo-
roacetamide was obtained, which was likely due to formation
of difluoroketene by fragmentation of the acid chloride (Scheme
4). To avoid ketene formation, acid 5 was first converted to
methyl ester 8 using methyl orthoformate and sulfuric acid. Ester
8 was then reacted with benzylamine to give amide 6 (Scheme
5).
Although the Reformatskii-Claisen sequence produced de-
sired acid 5, the process generated a large amount of ZnCl2
waste, offered relatively low yields, and was not ideal for large-
scale production. Trifluoroethyl allyl ethers have been used
widely as Claisen precursors by dehydrofluorination to produce
2,2-difluoropent-4-enal derivatives,5 which in turn could be
converted to pyrrolidine derivatives through a radical cyclization
Since iodolactamization6 does not usually give good results
with secondary amides,7 we were delighted to see high yields
obtained with secondary amide 6 (Scheme 8).8 Displacement
of iodide from lactam 7 with oxygenated nucleophiles was
unsuccessful. Even mild conditions by reaction with silver
trifluoroacetate resulted predominantly in elimination product
12. Given the difficulties with the substitution attempts, lactam
7 was treated with DBU to give a quantitative yield of enamide
12. The latter was treated with in situ-formed borane, followed
by H2O2, to achieve hydroboration and reduction in one pot to
give alcohol 13. A protecting group change converted 13 to
the requisite Boc amino alcohol 14. Finally, oxidation of alcohol
14 with NaClO2, catalytic NaClO, and TEMPO gave carboxylic
(5) (a) Metcalf, B. W.; Jarvi, E. T.; Burkhart, J. P. Tetrahedron Lett.
1985, 26, 2861. (b) Garayt, M. R.; Percy, J. M. Tetrahedron Lett. 2001,
42, 6377.
(6) Knapp, S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006.
(7) Knapp, S.; Gibson, F. S.; Choe, Y. H. Tetrahedron Lett. 1990, 31,
5397.
(4) Britton, Thomas C. U.S. Patent 5,618,951, 1997.
J. Org. Chem, Vol. 71, No. 15, 2006 5469

Chen et al.
SCHEME 8 a
°C, followed by hydrolysis with aqueous NaOH, provided nearly
racemic 1 (6% ee) suitable for reuse.
Conclusions
Difluorodimethylproline derivative (S)-1 was prepared from
commercially available trifluoroacetaldehyde methyl hemiacetal
in 12 steps. Hazardous fluorination was avoided, and the overall
yield was greater than 28%. A new synthesis of key intermediate
amide 6 from trifluoroacetaldehyde methyl hemiacetal through
an elimination-Claisen rearrangement sequence was developed.
a Key: (a) (i) TMSOTf, NEt3, hexanes, (ii) I2, CH3CN, 90%; (b) DBU,
EtOAc, reflux; (c) (i) NaBH4, BF3‚Et2O, THF, (ii) 50% H2O2, 50% NaOH;
(d) Pd/C, H2, aq HCl, THF; (e) Boc2O, 2 N NaOH; (f) NaClO2, NaClO,
TEMPO, 66% from 7.
Experimental Section
General Experimental Information. 1H NMR (300 MHz), 13
C
NMR (75 MHz), and 19F NMR (282 MHz) spectra were recorded
with a 300 MHz NMR spectrometer. 19F data are reported in ppm
relative to C6H5F, and the 19F spectra were 1H-coupled unless
otherwise specified. High-resolution mass spectral analyses were
conducted using a mobile phase system of 1:1 H2O/MeOH + 0.1%
HCO2H. GC-MS analyses were conducted with a 30.0 m × 250
µm × 0.25 µm column and a 50-250 °C temperature gradient.
Achiral HPLC analyses were performed on a 3 µm ODS(3) 100A
column (100 × 4.6 mm), 35 °C column chamber, 1.0 mL/min flow
rate, 254 nm UV detection, and a linear gradient with 0.1% CF3s-
CO2H /H2O (solvent A) and 0.1% CF3CO2H/CH3CN (solvent B)
[gradient: 90% solvent A (0 min) f 35% solvent A (10 min) f
10% solvent A (12 min) f 10% solvent A (15 min)]. Chiral HPLC
analyses were performed with a 4.6 × 150 mm column, 40 °C
column chamber, 0.5 mL/min flow rate, 205 nm UV detection, an
isocratic solvent system consisting of 0.1% CF3CO2H/H2O (75%)
and CH3CN (25%), and a total run time of 25 min. TLC analyses
were conducted with precoated silica gel plates [Si250F (250 µm)],
which were visualized under UV light and then stained with a
solution of phosphomolybdic acid/ethanol. Melting points were
uncorrected.
SCHEME 9 a
a Key: (a) (i) (1R,2S)-(-)-2-amino-1,2-diphenylethanol, CH3CN/EtOH
(9:1), (ii) CH3CN/EtOH (9:1), 50 °C, 70%; (b) (i) 1 N HCl, EtOAc, (ii)
crystallize from CH3OH/H2O, 86%; (c) (i) CDI, THF, (ii) DABCO, 50 °C;
(d) NaOH (aq), 82%.
Preparation of 3-Methylbut-2-enyl 2-Chloro-2,2-difluoroac-
etate (4). 3-Methylbut-2-en-1-ol (11.1 mL; 109 mmol) and NEt3
(24.0 mL; 172 mmol) were dissolved in MTBE (80 mL). DMAP
(0.2 g; 1.6 mmol) was added, and the solution was then cooled to
-10 °C. Chlorodifluoroacetic anhydride (20.0 mL; 115 mmol) was
added dropwise such that the internal temperature remained between
-10 and 0 °C. After being stirred at -10 °C for 20 min, the solution
was warmed to ambient temperature and stirred overnight. The
solution was cooled to 0 °C and was then quenched with 20%
aqueous citric acid (100 mL). The layers were separated, and the
aqueous fraction was then extracted with MTBE (100 mL). The
combined MTBE extracts were washed sequentially with 20%
aqueous citric acid (100 mL), saturated aqueous NaCl (100 mL),
saturated aqueous NaHCO3 (100 mL), and saturated aqueous NaCl
(100 mL). After drying over Na2SO4, concentration in vacuo gave
22.1 g (100%) of 4 as a light-brown liquid: 1H NMR (300 MHz,
CDCl3) δ 5.38-5.46 (m, 1H), 4.85 (d, J ) 7.4, 2H), 1.82 (s, 3H),
1.78 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.5 (t, J ) 34.0
Hz), 142.7, 117.4 (t, J ) 300.7 Hz), 116.6, 65.3, 25.9, 18.2; 19F
NMR (282 MHz, CDCl3) δ 49.4 (s); IR (neat) 1775, 1298, 1165,
acid (()-1. Because the late intermediates are either low melting
solids or exhibit significant water solubility, no purification was
conducted after compound 7. A simple acid-base extractive
workup was effective at removing virtually all impurities and
yielded (()-1 in 66% yield from iodolactam 7.
(S)-1 was prepared by a classical chemical resolution with
(1R,2S)-(-)-2-amino-1,2-diphenylethanol in 30% chemical yield
and 100% ee (Scheme 9). A procedure for recycling the
undesired enantiomer was also established. (R)-Enriched 1 (86%
ee), from the supernatant of 15, was converted to the corre-
sponding acyl imidazole 16. Exposure of 16 to DABCO at 50
(8) We believe that during silyl imidate formation there was an
equilibrium between A and B when an R-proton was available. In some
cases, we were able to isolate R-iodoamide D from the reaction mixture
when an R-proton was present. Since no R-proton exists in amide 6, only
the pathway to C (and thus 7) was possible.
1119, 960, 900, 814, 728 cm-1
.
Preparation of 2,2-Difluoro-3,3-dimethylpent-4-enoic Acid
(5). TMS-Cl (129 mL; 1.02 mol) was added to a suspension of Zn
dust (66.9 g; 1.02 mol) and DMI (40 mL), and the mixture was
then cooled to 15 °C. A solution of 4 (76.1 g of 89% purity; 341
mmol) and DMI (10 mL) was added such that the internal
temperature remained between 15 and 20 °C. The mixture was
stirred at 0 °C for 30 min and then at ambient temperature for 24
h, while being monitored by GC-MS. The mixture was heated at
100 °C for 7 h, while volatiles were removed. The mixture was
cooled to room temperature and was then quenched with 5 N HCl
(180 mL). After being stirred for 30 min, the mixture was filtered
5470 J. Org. Chem., Vol. 71, No. 15, 2006

Synthesis of a 4,4-Difluoro-3,3-Dimethylproline DeriVatiVe
and the solid was then washed with EtOAc (100 mL). The combined
filtrate and wash were extracted with EtOAc (4 × 150 mL). The
combined EtOAc extracts were washed with half-saturated aqueous
NaCl (300 mL) and saturated aqueous NaCl (300 mL) and were
then dried over Na2SO4. After concentration in vacuo, 75.8 g of
crude 5 was obtained as a dark liquid. 1H NMR indicated
approximately 50% purity, which was appropriate for the next step.
Corrected for purity, the yield was ∼68%: 1H NMR (300 MHz,
CDCl3) δ 8.23 (br s, 1H), 5.91-6.00 (m, 1H), 5.23 (s, 1H), 5.18
(d, J ) 6.8 Hz, 1H), 1.24 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
168.1 (t, J ) 33.6 Hz), 139.2 (t, J ) 3.7 Hz), 118.1 (t, J ) 257.2
Hz), 116.3, 43.4 (t, J ) 21.4 Hz), 20.9 (t, J ) 3.9 Hz); 19F NMR
(282 MHz, CDCl3) δ -1.32 (s); IR (neat) 3094, 2989, 1747, 1470,
1419, 1388, 1277, 1229, 1183, 1112, 1067, 1036, 998, 926, 778,
orange oil: 1H NMR (300 MHz, CDCl3) δ 5.34-5.42 (m, 1H),
4.66 (q, J ) 4.2 Hz, 1H), 4.25 (d, J ) 7.1 Hz, 2H), 3.53 (s, 3H),
1.80 (s, 3H), 1.72 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 139.6,
122.2 (q, J ) 284.9 Hz), 119.5, 97.2 (q, J ) 34.6 Hz), 65.2, 55.5,
26.1, 18.3; 19F NMR (282 MHz, CDCl3) δ 33.0 (d, J ) 4.2 Hz);
IR (neat) 1282, 1174, 1156, 1113, 1079, 988, 715 cm-1. Charac-
teristic data for 3-methyl-1-(2,2,2-trifluoro-1-(3-methylbut-2-enyl-
oxy)ethoxy)but-2-ene impurity: 1H NMR (300 MHz, CDCl3) δ
5.34-5.41 (m, 2H), 4.75 (q, J ) 4.3 Hz, 1H), 4.23 (d, J ) 7.0 Hz,
4H), 1.80 (s, 6H), 1.72 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
139.2, 122.4 (q, J ) 284.8 Hz), 119.8, 95.6 (q, J ) 34.5 Hz), 64.9,
26.1, 18.3; 19F NMR (282 MHz, CDCl3) δ 33.0 (d, J ) 4.3 Hz);
Preparation of N-Benzyl-2,2-difluoro-3,3-dimethylpent-4-ena-
mide (6) (Elimination-Claisen Procedure). A solution of crude
10 (5.00 mL; ∼25 mmol) and THF (20 mL) was cooled to -70
°C. n-BuLi (21.0 mL of a 2.5 M solution in hexane; 52.5 mmol)
was added slowly, such that the internal temperature remained
between -70 and -50 °C. The resulting mixture was stirred at
-75 °C for 15 min. Benzylamine (5.50 mL; 50.0 mmol) was added
slowly, such that the internal temperature remained between -70
and -55 °C. The reaction was then warmed to ambient temperature
for 0.5 h, at which time GC-MS analysis showed complete Claisen
rearragement and amidation. The mixture was cooled to 0 °C, and
1.7 N HCl (70 mL) was then added. The mixture was extracted
with EtOAc (75 mL). The organic fraction was washed sequentially
with 0.5 N HCl (75 mL), H2O (75 mL), saturated aqueous NaHCO3
(75 mL), and saturated aqueous NaCl (75 mL) and was then dried
over Na2SO4. After concentration in vacuo, 4.95 g (80% over two
steps) of 6 was obtained as a brown oil.
709, 672 cm-1
.
Preparation of Methyl 2,2-Difluoro-3,3-dimethylpent-4-enoate
(8). A mixture of crude 5 (47.2 g of ∼61% purity; 175 mmol),
HC(OMe)3 (57.5 mL; 526 mmol), MeOH (57.5 mL), and H2SO4
(3.5 mL) was heated at 35 °C for 19 h. The mixture was cooled to
5 °C with an ice bath and was then quenched with saturated aqueous
NaHCO3 (300 mL). The mixture was extracted with EtOAc (150
mL), and the resulting aqueous fraction was then extracted with
EtOAc (3 × 60 mL). The combined EtOAc extracts were washed
with saturated aqueous NaHCO3 (3 × 100 mL) and then with
saturated aqueous NaCl (3 × 100 mL). After drying over Na2SO4
and concentration in vacuo, 32.6 g crude of 8 was obtained as a
dark oil. 1H NMR indicated approximately 85% purity, which was
appropriate for the next step. Corrected for purity, the yield was
∼88%: 1H NMR (300 MHz, CDCl3) δ 5.96 (dd, J ) 10.9, 17.3
Hz, 1H), 5.21 (d, J ) 10.7 Hz, 1H), 5.17 (d, J ) 17.6 Hz, 1H),
3.85 (s, 3H), 1.22 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 164.6 (t,
J ) 33.4 Hz), 139.6 (t, J ) 3.6 Hz), 118.3 (t, J ) 257.5 Hz), 115.8,
53.2, 43.5 (t, J ) 21.5 Hz), 21.0 (t, J ) 3.9 Hz); 19F NMR (282
MHz, CDCl3) δ -0.85 (s); IR (neat) 1764, 1307, 1113, 1066, 1040,
Preparation of (()-1-Benzyl-3,3-difluoro-5-(iodomethyl)-4,4-
dimethylpyrrolidin-2-one (7). TMS-OTf (4.80 mL; 26.6 mmol)
was added dropwise to a -3 °C solution of 6 (5.00 g; 19.7 mmol),
NEt3 (4.10 mL; 29.6 mmol), and hexanes (40 mL), such that the
internal temperature did not rise above 6 °C. The mixture was
warmed to ambient temperature and was then stirred for 1 h. The
suspension was filtered, and the solid was then washed with hexanes
(10 mL). The combined filtrate and wash were concentrated in
vacuo. The residue was dissolved in THF (10 mL) and was then
cooled to 0 °C. I2 (6.01 g; 23.7 mmol) was added, and after being
stirred at 0 °C for 5 min, the mixture was stirred at ambient
temperature for 1.5 h. The mixture was cooled to 0 °C and was
quenched with a solution of NaHSO3 (0.75 g) and H2O (10 mL).
After being stirred vigorously for 10 min, the mixture was extracted
with EtOAc (50 mL). The organic fraction was washed with
saturated aqueous NaHCO3 (50 mL) and then with saturated
aqueous NaCl (50 mL). After drying over Na2SO4 and concentration
in vacuo, 12.5 g of crude 7 was obtained as an oil. Crude 7 was
dissolved in 95% EtOH (20 mL), and H2O (10 mL) was then added
dropwise to the stirring solution. After the mixture was stirred for
10 min, additional H2O (10 mL) was slowly added. The resulting
slurry was cooled to -5 °C and, after stirring for 5 min, was filtered.
The crystals were washed with 30% EtOH (20 mL), and were then
dried under vacuum at 55 °C overnight to give 6.68 g (89.4%) of
7 as a brown solid: mp ) 76-77 °C; 1H NMR (300 MHz, CDCl3)
δ 7.28-7.42 (m, 5H), 5.11 (d, J ) 14.8 Hz, 1H), 4.30 (dd, J )
2.5, 14.8 Hz, 1H), 3.39-3.45 (m, 1H), 3.16-3.28 (m, 1H), 1.28
(d, J ) 2.0 Hz, 3H), 1.01 (d, J ) 2.8 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 164.5 (dd, J ) 29.6, 32.0), 135.6, 130.2, 129.8, 129.6,
119.4 (dd, J ) 252.1, 257.7), 65.1 (J ) 3.9 Hz), 46.7, 43.9 (t, J )
19.4), 23.3 (dd, J ) 3.1, 7.6 Hz), 16.7 (d, J ) 7.7 Hz), 0.0; 19F
NMR (282 MHz, CDCl3) δ 1.91 (d, J ) 265.6 Hz), -12.4 (app dt,
J ) 265.7, 2.5 Hz); MS (CI) m/z 380.0339 (380.0323 calcd for
C14H17NOF2I, M + H+); IR (neat) 1715, 1450, 1330, 1269, 1169,
926, 805, 738, 680 cm-1
.
Preparation of N-Benzyl-2,2-difluoro-3,3-dimethylpent-4-ena-
mide (6) (Reformatskii-Claisen Procedure). Benzylamine (36.2
mL; 331 mmol) was added to a mixture of crude 8 (39.4 g of ∼75%
purity; 166 mmol). The resulting mixture was stirred overnight at
ambient temperature for 23 h, while being monitored by GC. The
mixture was adjusted to pH 2-3 with 1 N HCl (∼300 mL required).
The mixture was extracted with EtOAc (125 mL), and the resulting
aqueous fraction was extracted with EtOAc (3 × 75 mL). The
combined EtOAc extracts were washed sequentially with 1 N HCl
(100 mL), saturated aqueous NaHCO3 (100 mL), and saturated
aqueous NaCl (100 mL). After drying over MgSO4 and concentra-
1
tion in vacuo, 40.1 g of crude 6 was obtained as an oil. H NMR
indicated approximately 85% purity, which was appropriate for the
next step. Corrected for purity, the yield was ∼81%: 1H NMR
(300 MHz, DMSO-d6) δ 9.11 (br s, 1H), 7.21-7.37 (m, 5H), 5.95
(dd, J ) 10.7, 17.6 Hz, 1H), 5.16 (d, J ) 5.7 Hz, 1H), 5.11 (s,
1H), 4.32 (d, J ) 6.1 Hz, 2H), 1.14 (s, 6H); 13C NMR (75 MHz,
DMSO-d6) δ 163.1 (t, J ) 29.6), 140.0 (t, J ) 3.9 Hz), 138.9,
128.6, 127.7, 127.3, 119.1 (t, J ) 257.7 Hz), 115.5, 43.1 (t, J )
21.9 Hz), 42.6, 21.1 (t, J ) 3.9 Hz); 19F NMR (282 MHz, CDCl3)
δ -1.25 (s); MS (CI) m/z 254.1342 (254.1356 calcd for C14H18-
NOF2, M + H+); IR (neat) 3324, 1698, 1681, 1541, 1130, 1097,
1080, 973, 923, 719, 695, 677 cm-1
.
Preparation of (()-3-Methyl-1-(2,2,2-trifluoro-1-methoxy-
ethoxy)but-2-ene (10). A mixture of trifluoroacetaldehyde methyl
hemiacetal (35.0 g; 269 mmol), K2CO3 (93.0 g; 673 mmol), n-Bu4-
NBr (4.3 g; 13.5 mmol), and THF (160 mL) was cooled to 0 °C.
1-Bromo-3-methylbut-2-ene (34.1 mL; 296 mmol) was added, and
the mixture was then allowed to warm to ambient temperature and
stir for 18 h, while being montiored by GC-MS. The mixture was
filtered, and the solids were washed with THF (100 mL). The
combined filtrate and wash were concentrated in a vacuum to give
51.2 g of a ∼ 20:1 mixture of 10 and the bis-allyl acetal [3-methyl-
1-(2,2,2-trifluoro-1-(3-methylbut-2-enyloxy)ethoxy)but-2-ene] as an
1083, 1031, 979, 746, 693 cm-1
.
Preparation of 1-Benzyl-3,3-difluoro-4,4-dimethyl-5-methyl-
enepyrrolidin-2-one (12). DBU (5.90 mL; 39.3 mmol) was added
to a solution of 7 (7.46 g; 19.7 mmol) and EtOAc (15 mL) at
ambient temperature. The mixture was heated at reflux for 1.5 h,
while being monitored by HPLC. The mixture was cooled to room
J. Org. Chem, Vol. 71, No. 15, 2006 5471

Chen et al.
temperature and quenched with 2 N HCl (20 mL). The mixture
was then extracted with EtOAc (50 mL). The EtOAc extract was
washed sequentially with 0.5 N HCl (50 mL), saturated aqueous
NaHCO3 (50 mL), and saturated aqueous NaCl (50 mL). After
drying over Na2SO4 and concentration in vacuo, 4.97 g (100%) of
crude 12 was obtained as an oil and used as is in the next step: 1H
NMR (300 MHz, CDCl3) δ 7.21-7.39 (m, 5H), 4.77 (s, 2H), 4.43-
4.45 (m, 1H), 4.36 (d, J ) 3.0 Hz, 1H), 1.30 (t, J ) 1.6 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 164.1 (t, J ) 31.2 Hz), 150.1 (t, J
) 3.5 Hz), 135.0, 129.2, 128.3, 127.5, 117.9 (t, J ) 255.0 Hz),
88.5, 44.6, 43.1 (t, J ) 20.5 Hz), 21.1 (t, J ) 5.6 Hz); 19F NMR
(282 MHz, CDCl3) δ -7.04 (s); MS (CI) m/z 252.1204 (252.1200
calcd for C14H16NOF2, M+H+); IR (neat) 1744, 1655, 1390, 1288,
(266.1568 calcd for C12H22NO3F2, M + H+); IR (neat) 3425, 2978,
2897, 1677, 1473, 1393, 1368, 1353, 1250, 1164, 1131, 1105, 1090,
1045, 1010, 908, 895, 857, 774, 715, 703 cm-1
.
Preparation of (()-1-(tert-Butoxycarbonyl)-4,4-difluoro-3,3-
dimethylpyrrolidine-2-carboxylic Acid [(()-1]. TEMPO (0.07 g;
0.44 mmol), KH2PO4 (1.21 g; 8.89 mmol), and a solution of NaClO2
(3.00 g of ∼80% purity; 26.5 mmol) and H2O (5 mL) were
sequentially added to a solution of crude 14 (4.70 g; 17.7 mmol)
and CH3CN (5 mL) at ambient temperature. The mixture was cooled
to 0 °C and stirred for 5 min. An aqueous solution of NaClO (1.0
mL of a 6.15% aqueous solution; 0.83 mmol) was added. The
resulting dark purple mixture was stirred at 0 °C for 3 h while
monitoring by TLC (silica gel; 1:4 EtOAc/hexanes). The reaction
was quenched with 2% aqueous NaHSO3 (25 mL) and was adjusted
to pH 10 with 2 N NaOH. The mixture was washed with EtOAc
(30 mL). The resulting aqueous fraction was filtered on Celite, and
the filtrate was stirred under house vacuum (∼30 mmHg) for 2 h
to remove volatiles and then adjusted to pH 3 with 1 N HCl to
form a white suspension. After filtration, H2O washing, and drying
under vacuum at 55 °C overnight, 3.64 g (66% over four steps
from 7) of 1 was obtained as a white solid. The spectroscopic data
was identical to that for (S)-1.
1156, 1091, 1065, 835, 754, 696 cm-1
.
Preparation of (()-(1-Benzyl-4,4-difluoro-3,3-dimethylpyr-
rolidin-2-yl)methanol (13). NaBH4 (1.68 g; 44.3 mmol) was added
to a solution of 12 (4.96 g; 19.7 mmol) and THF (40 mL) at ambient
temperature. The mixture was cooled to -4 °C, and BF3‚OEt2 (10.0
mL) was then added such that the internal temperature remained
< 0 °C. The resulting mixture was stirred at -10 to 0 °C for 2.5
h, while being monitored by HPLC. MeOH (5 mL) was added such
that the internal temperature remained <5 °C. 50% H2O2 (10 mL)
was then added such that the internal temperature remained <0
°C. After an additional 5 min, 50% NaOH (12 mL) was added (pH
> 12). The suspension was stirred for 10 min and was then extracted
with EtOAc (50 mL). The EtOAc extract was washed with H2O
(50 mL) and then with saturated aqueous NaCl (50 mL). After
drying over Na2SO4 and concentration in vacuo, 4.58 g (91%) of
crude 13 was obtained as an oil and was used as is in the next
step: 1H NMR (300 MHz, CDCl3) δ 7.26-7.40 (m, 5H), 4.11 (d,
J ) 13.3 Hz, 1H), 3.77-3.82 (m, 1H), 3.63-3.68 (m, 1H), 3.51
(d, J ) 13.3 Hz, 1H), 3.31 (ddd, J ) 8.7, 11.9, 20.8 Hz, 1H), 2.88
(ddd, J ) 8.6, 11.8, 19.6 Hz, 1H), 2.57 (br s, 1H), 1.15 (d, J ) 2.3
Hz, 3H), 1.12 (d, J ) 2.3 Hz, 3H); 13C NMR (75 MHz, CD3OD)
δ 140.6, 130.4 (dd, J ) 249.5, 257.1 Hz), 130.1, 129.8, 128.6,
73.9 (d, J ) 3.9 Hz), 63.4, 60.9, 59.8 (t, J ) 28.2 Hz), 46.6 (t, J
) 20.0 Hz), 20.7 (d, J ) 8.5 Hz), 17.8 (dd, J ) 2.8, 7.7 Hz); 19F
NMR (282 MHz, CDCl3) δ 4.62 (dt, J ) 227.1, 20.7 Hz), -2.57
(d, J ) 226.6 Hz); MS (CI) m/z 256.1500 (256.1513 calcd for
C14H19NOF2, M + H+); IR (neat) 3419, 2937, 1453, 1192, 1071,
Preparation of (2S,3R)-2,3-Diphenyl-3-hydroxyethylammo-
nium (S)-1-(tert-Butoxycarbonyl)-4,4-difluoro-3,3-dimethylpyr-
rolidine-2-carboxylate (15). (1R,2S)-(-)-2-Amino-1,2-diphenyl-
ethanol (3.82 g; 17.9 mmol) was added to a solution of (()-1 (10.0
g; 35.8 mmol), CH3CN (90 mL), and absolute EtOH (10 mL) at
ambient temperature. The resulting slurry was stirred at ambient
temperature for 24 h. The suspension was filtered, and the white
solid was washed with CH3CN (50 mL) and was then dried under
vacuum at 55 °C overnight to give 7.71 g of 15 with 53.0% de by
chiral HPLC. This material was suspended in 9:1 CH3CN/EtOH
(77 mL) and was then heated at 50 °C for 24 h. After cooling to
ambient temperature, the suspension was filtered and the solid was
dried under vacuum at 55 °C overnight to give 6.20 g (35.1%) of
15 as a white solid: mp ) 179-180 °C; chiral HPLC 96.6% de;
1H NMR (300 MHz, CD3OD) δ 7.19-7.35 (m, 8H), 7.08-7.15
(m, 2H), 5.20 (d, J ) 4.2 Hz, 1H), 4.45 (d, J ) 4.2 Hz, 1H), 3.93-
3.99 (m, 1H), 3.72-3.90 (m, 2H), 1.45-1.48 (m, 9H), 1.26 (s,
3H), 1.22 (s, 3H); 13C NMR (75 MHz, DMSO-d6) major rotamer
δ 172.7, 154.1, 142.0, 137.1, 130.9 (one central peak of CF2 AB
q), 129.1, 127.8, 127.7, 127.6, 127.1, 126.7, 124.2 (one central peak
of CF2 AB q), 79.4, 73.6, 69.6, 60.5, 51.3 (t, J ) 31.6 Hz), 41.2 (t,
J ) 20.5 Hz), 28.3, 21.6-21.8 (m), 18.5-18.7 (m), minor rotamer
δ 172.3, 153.7, 69.3, 51.9 (t, J ) 31.7 Hz), 44.5 (t, J ) 20.3 Hz),
28.4, 21.8-22.1 (m), 18.3-18.5 (m); 19F NMR (282 MHz, CD3-
OD, 1H-decoupled) major rotamer δ -0.56 (AB q, J ) 229.1 Hz,
∆ν ) 1099.0 Hz); minor rotamer δ 0.31 (AB q, J ) 229.2 Hz, ∆ν
) 510.4 Hz); IR (neat) 3337, 2978, 1683, 1587, 1505, 1416, 1380,
1368, 1307, 1151, 1129, 1093, 1048, 911, 901, 769, 751, 718, 703
1027, 900, 735, 698 cm-1
.
Preparation of (()-tert-Butyl 4,4-Difluoro-2-(hydroxymethyl)-
3,3-dimethylpyrrolidine-1-carboxylate (14). A suspension of
crude 13 (4.58 g; 17.9 mmol) and 0.6 N HCl (50 mL) was stirred
at 50 °C for 5 min. Activated charcoal (3 g) was added, and the
mixture was then stirred at 50 °C for 5 min. The mixture was filtered
through Celite, and the filter was then washed with H2O (10 mL)
and THF (30 mL). Pd/C (10%, 0.5 g wet) was added to the
combined filtrate and wash, and the resulting mixture was hydro-
genated with a Parr shaker (50 psi H2). After hydrogenating
overnight and monitoring by TLC (silica gel; 1:4 EtOAc/hexanes),
the mixture was then filtered on Celite. The THF was removed by
concentration in a vacuum (∼30 mmHg), and the resulting aqueous
mixture was adjusted to ∼pH 10 with 2 N NaOH. Boc2O (4.90
mL; 21.5 mmol) was added, and the mixture was then stirred at
ambient temperature for 5 h while being monitored by TLC (silica
gel; 1:4 EtOAc/hexanes). Glycine (1.34 g; 17.8 mmol) was added,
and after being stirred at ambient temperature overnight, the mixture
was extracted with EtOAc (2 × 50 mL). The combined organic
extracts were washed with saturated aqueous NaHCO3 (100 mL)
and then with saturated aqueous NaCl (50 mL). After drying over
Na2SO4 and concentration in a vacuum, 4.70 g (99%) of crude 14
was obtained as an oil and was used as is in the next step: 1H
NMR (300 MHz, CDCl3) δ 4.91 (br s, 1H), 3.58-3.77 (m, 5H),
1.48 (s, 9H), 1.16 (s, 3H), 1.00 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 157.0, 126.9 (t, J ) 251.9), 82.0, 68.9, 63.7, 52.5 (t, J ) 31.9
Hz), 44.9 (t, J ) 20.3 Hz), 28.7, 19.8 (d, J ) 6.3 Hz), 16.6 (d, J
) 3.8 Hz); 19F NMR (282 MHz, CDCl3) δ 0.03 (dt, J ) 232.0,
17.3 Hz), 4.50 (app dt, J ) 231.7, 8.2 Hz); MS (CI) m/z 266.1591
cm-1
.
Preparation of (S)-1-(tert-Butoxycarbonyl)-4,4-difluoro-3,3-
dimethylpyrrolidine-2-carboxylic Acid [(S)-1]. Compound 15
(4.00 g; 8.12 mmol) was partitioned between EtOAc (90 mL) and
1 N HCl (90 mL) while being warmed to 30 °C to complete
dissolution of 15, and the resulting layers were separated. The
EtOAc fraction was sequentially washed with H2O (2 × 50 mL)
and saturated aqueous NaCl (50 mL) and was then dried over
MgSO4, filtered, and concentrated to give 2.20 g (96.9%) of crude
(S)-1. Crude (S)-1 was dissolved in CH3OH (6.6 mL) at ambient
temperature, and H2O (11.2 mL) was then slowly added to effect
crystallization. The resulting crystal slurry was stirred at ambient
temperature overnight. The suspension was filtered, and the solid
was washed with H2O (10 mL) and was then dried under vacuum
at 50 °C overnight to give 1.95 g (85.9%) of (S)-1 as white
crystals: mp ) 143-144 °C; chiral HPLC 100% ee; 1H NMR (300
MHz, DMSO-d6) δ 12.90 (br s, 1H), 3.95 (s, 1H), 3.74-3.87 (m,
2H), 1.41 (s, 3H), 1.36 (s, 6H), 1.22 (app d, J ) 1.6 Hz, 3H), 1.04
(app d, J ) 1.5 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) major
5472 J. Org. Chem., Vol. 71, No. 15, 2006

Synthesis of a 4,4-Difluoro-3,3-Dimethylproline DeriVatiVe
rotamer δ 170.8, 153.3, 126.8 (dd, J ) 251.2, 253.9 Hz), 80.3,
67.8, 51.0 (t, J ) 31.5 Hz), 45.6 (t, J ) 21.2 Hz), 28.1, 21.4 (app
dd, J ) 1.9, 6.6 Hz), 17.9 (app dd, J ) 1.4, 6.5 Hz), minor rotamer
δ 170.3, 153.7, 127.3 (dd, J ) 252.2, 253.8 Hz), 80.8, 67.3, 51.5
(t, J ) 31.9 Hz), 44.9 (t, J ) 21.1 Hz), 28.3, 21.6 (app dd, J ) 1.5,
7.1 Hz), 17.7 (d, J ) 6.1 Hz); 19F NMR (282 MHz, DMSO-d6, 1H
decoupled) major rotamer δ 0.32 (AB q, J ) 227.4 Hz, ∆ν ) 354.4
Hz), minor rotamer δ 1.10 (AB q, J ) 227.1 Hz, ∆ν ) 578.0 Hz);
MS (CI) m/z 280.1374 (280.1360 calcd for C12H20NO4F2, M + H+);
IR (neat) 2983, 1750, 1735, 1645, 1472, 1424, 1369, 1202, 1157,
was then heated to 50 °C. After the mixture was stirred for 2 days
at 50 °C, chiral HPLC revealed a 47:53 ratio of S/R enantiomers.
Aqueous NaOH (8.0 mL of a 1.5 M solution) was added, and the
hydrolysis was monitored by HPLC. After hydrolysis was complete,
the reaction mixture was diluted with MTBE (20 mL) and H2O
(20 mL). The biphasic mixture was acidified to ∼pH 1 with concd
HCl, and the layers were separated. The organic phase was washed
with H2O (10 mL) and then with saturated aqueous NaCl (10 mL).
After drying over MgSO4, filtration, and concentration, 1.64 g (82%)
of 1-(tert-butoxycarbonyl)-4,4-difluoro-3,3-dimethylpyrrolidine-2-
carboxylic acid was obtained as a white solid. Chiral HPLC revealed
a 47:53 ratio of S/R enantiomers. The spectroscopic data was
identical to that for (S)-1.
1094, 908, 858, 765, 705 cm-1
.
Preparation of (()-1-(tert-Butoxycarbonyl)-4,4-difluoro-3,3-
dimethylpyrrolidine-2-carboxylic Acid [(()-1] by Racemization
of an (R)-Enriched Mixture. (R)-Enriched 1-(tert-butoxycarbonyl)-
4,4-difluoro-3,3-dimethylpyrrolidine-2-carboxylic acid 1 (2.00 g;
7.16 mmol; 86% ee) was dissolved in anhydrous THF (20 mL) at
ambient temperature. CDI (1.28 g; 7.88 mmol) was added, and the
solution was stirred at ambient temperature, while being monitored
by HPLC. Once conversion to the acyl imidazole was complete
(∼1 h), DABCO (0.803 g; 7.16 mmol) was added, and the solution
Supporting Information Available: NMR spectra for obtained
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO060057P
J. Org. Chem, Vol. 71, No. 15, 2006 5473