Synthesis of Boc-protected cis- and trans-4-trifluoromethyl-D-prolines

Article abstract of DOI:10.1039/b206719f

Both Boc-protected trans- and cis-4-trifluoromethyl prolines were synthesized starting from L-serine simultaneously. In our synthetic route, the key intermediate 4 was obtained through the reaction of Garner's aldehyde 1 with ylide 2 followed by trifluoro

Full text of DOI:10.1039/b206719f

View Article Online / Journal Homepage / Table of Contents for this issue
Synthesis of Boc-protected cis- and trans-4-trifluoromethyl-D-
prolines
Xiao-long Qiua and Feng-ling Qing*a,b
1
a Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China.
E-mail: flq@pub.sioc.ac.cn; Fax: ϩ86-21-64166128
b College of Chemistry and Chemical Engineering, Donghua University, 1882 West Yanan Lu,
Shanghai 200051, China
Received (in Cambridge, UK) 10th July 2002, Accepted 30th July 2002
First published as an Advance Article on the web 23rd August 2002
Both Boc-protected trans- and cis-4-trifluoromethyl prolines were synthesized starting from -serine simultaneously.
In our synthetic route, the key intermediate 4 was obtained through the reaction of Garner’s aldehyde 1 with ylide 2
followed by trifluoromethylation with FSO2CF2COOMe–CuI. After hydrogenation followed by reduction of 4, the
alcohol 5 was obtained in low diastereoselectivity, however, the two diastereoisomers could be separated easily by
flash chromatography in the following steps. The bromide 8b obtained from the alcohol 5 in a straightforward fashion
could not afford the desired cyclization product because of the strong electron-withdrawing properties of the
trifluoromethyl group and the low ability of bromide as a leaving group. Instead, mesylation of alcohols 12a and 12b
followed by treatment with potassium bis(trimethylsilyl)amide (KHMDS) afforded the desired cyclization products
13a and 13b respectively, which were transformed into Boc-protected cis- and trans-4-trifluoromethyl--prolines in a
straightforward fashion.
including Captopril13 and Enalapril.14 Their incorporation
Introduction
into bioactive peptides and proteins leads to constrained con-
Amino acids have excited interest for many years and are still
formations which are useful tools for establishing structure–
an area of current interest in the twenty-first century. Investi-
gations into the biological properties of amino acids have
been intensively prosecuted and have resulted in a dramatic
acceleration of activity and interest in synthesis of unusual
bioactivity relationships and for understanding biological
processes.11
Besides efficient asymmetric syntheses of 3-, 4-, 5-alkyl- and
aryl-substituted prolines,11,15 there are a number of methods
amino acids directed, first of all, at the creation of new
describing the preparation of fluorine-substituted prolines,
medicines and fine biochemicals.1 Among these unusual amino
especially optically pure 4-fluoro and 4,4-difluoroprolines, most
acids, fluorine-containing amino acids attract a great deal
of which were realized by fluorination of 4-hydroxyproline
of attention because of the similar geometry of fluorine-
containing amino acids to hydrocarbon patterns, the opposite
and 4-oxoproline with DAST.16 However, to the best of our
knowledge, except that Wakselman et al.17 reported the syn-
polarization of C–H and C–F bonds, the greater energy of the
thesis of racemic methyl N-tert-butyl-4-trifluoromethyl--
proline by means of a [2ϩ3] cycloaddition, there are few reports
of enantiomerically pure syntheses of 4-trifluoromethylproline
latter and the similar size of F (1.35) to O (1.40) and H (1.20).2
Once introduced, the strong carbon–fluorine bond is par-
ticularly resistant to metabolic transformation and the electro-
negativity of fluorine can have a significant effect on the basicity
because of the difficulties in stereospecific incorporation of a
trifluoromethyl group into proline.18
or acidity of neighboring groups and on the reactivity and
Recently, our attention has been focused on the preparation
stability of a molecule.3 In addition, as well as being used as
of enantiomerically pure fluorine-containing amino acids
starting from abundantly available natural products and on
the incorporation of these fluorine-containing amino acids
into peptides. In connection with our studies and the situation
biological tracers and mechanistic probes for investigations on
the structures and properties of enzymes,3 fluorinated amino
acids also play an important role in the control of blood
pressure, allergies and tumor growth and incorporation of
fluorine-containing amino acids provides a route to proteins
4
mentioned above, we were challenged to develop a new, simple
synthetic strategy for Boc-protected trans- and cis-4-trifluoro-
and peptides with unique structural and chemical features.5 For
methylprolines.19 Herein we describe the synthesis of Boc-
example, Tirrell6 and Kumar7 recently found that a fluorinated
protected trans- and cis-4-trifluoromethyl--prolines.
coil–coiled protein prepared from trifluoroleucine had en-
hanced thermal and chemical stability. Therefore, there is much
literature describing methods for the synthesis of fluorinated
Results and discussion
amino acids.8–10
Proline and substituted prolines are interesting targets as
they are considered to be constrained analogues of natural
amino acids11 and they are key amino acids in many naturally
occurring bioactive peptides such as gramicidin12 and have
been extensively used in the pharmaceutical industry, for
instance as angiotensin-converting enzyme (ACE) inhibitors,
On the basis of retrosynthetic analysis, the 4-trifluoromethyl-
proline structure can be reached from α-trifluoromethyl-α,β-
unsaturated esters obtained through trifluoromethylation of a
serine-derived α-bromoenoate, as outlined in Scheme 1.
Previous studies20 carried out in our laboratory on the syn-
thesis of α-trifluoromethyl-α,β-unsaturated esters showed that
2052
J. Chem. Soc., Perkin Trans. 1, 2002, 2052–2057
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b206719f

View Article Online
Scheme 1
Scheme 3
genations of 11a and 11b were carried out on 10% Pd/C to give
the alcohols 12a (99% yield) and 12b (91% yield) respectively.
As we expected, after mesylation of the alcohol groups of 12a
and 12b,30 the resulting mesylates were treated with KHMDS to
yield the desired cyclization products 13a (83% yield in two
steps) and 13b (80% yield in two steps) respectively. Removal
of the tert-butyldimethylsilyl groups in 13a and 13b with tetra-
butylammonium fluoride (TBAF) in THF afforded the alcohols
14a and 14b respectively. Finally, oxidation31 of the hydroxy-
methyl moieties of 14a and 14b to carboxylic acids with Jones
reagent in acetone provided Boc-protected trans-4-trifluoro-
methyl--proline 15a (56% yield) and cis-4-trifluoromethyl--
proline 15b (68% yield) respectively. The absolute configur-
ations of 15a and 15b could be deduced from Boc-protected
cis-4-trifluoromethyl--proline18,19 whose absolute configur-
Scheme 2
the key intermediate 4 could easily be reached through trifluoro-
methylation21 of α-bromo-α,β-unsaturated ester 3 obtained
through a Wittig reaction between bromo phosphorane 222 and
Garner’s aldehyde23 (Scheme 2).
With 4 in hand, reduction of the ester with DIBAL-H
in toluene at Ϫ50 ЊC to the alcohol was carried out, however,
the yield was low (30%). In our opinion, the trifluoromethyl
group seemed to be responsible for the low yield because it
could cause defluorination through a similar Michael addition
reaction.24 Fortunately, initial hydrogenation of the double
bond of 4 with Raney-Ni followed by reduction25 of the ester
group with lithium aluminium hydride (LAH) afforded the
desired product 5 in 94% yield. The syn/anti ratio was deter-
mined to 35/65 according to 19F NMR. Replacement of the
hydroxy functionality of 5 by bromide (PPh3, Et3N, CBr4,
THF)26 was performed and 6 was obtained in 95% yield. The
hydrolysis of the hemiaminal moiety of 6 was investigated.
Initially, treatment of 6 with I2–MeOH27 and TsOHؒH2O–
MeOH28 afforded the product 7 in low yield. We were pleased
to find that the reaction of 6 with acetic acid (80% aqueous
solution )11,29 at 50 ЊC for 24 h gave the product 7 in 74% yield.
Slightly surprisingly, the two diastereoisomers of 7 could be
easily separated by flash chromatography (hexane–ethyl acetate
10 : 1 then 5 : 1). Benzoylation of the alcohol group of 7b gave
the cyclization precursor 8b as a white solid in 82% yield. How-
ever, cyclization of 8b did not occur in THF at 0 ЊC or room
temperature, using KHMDS and LiHMDS as the base. When
stronger bases, NaH and t-BuOK, were used, hydrolysis of the
ester group and dehydrobromination occurred. In our opinion,
the strong electron-withdrawing properties of the trifluoro-
methyl group and the weak ability of bromide as a leaving
group seemed to be responsible for the failure of the cyclization
of 8b (Scheme 3).
1
ation was determined by X-ray and NOE studies. H NMR,
19F NMR, 13C NMR, IR, MS of 15b were identical to those
of Boc-protected cis-4-trifluoromethyl--proline, but the optical
rotation of 15b ([α]2D0 = ϩ79 (c 0.98, CHCl3)) was opposite to
that of Boc-protected cis-4-trifluoromethyl--proline ([α]2D0
=
Ϫ77.6 (c 0.70, CHCl3))19 which demonstrated that they are
enantiomers. Furthermore, NOESY experiments on 15a
showed that the 2-H was trans to 4-H.
In summary, we have developed a methodology for the first
preparation of both cis- and trans-4-trifluoromethyl--proline
simultaneously. Most noteworthy is the use of α-trifluoro-
methyl-α,β-unsaturated ester 4 as the key intermediate and that
the replacement of bromide by mesylate as the leaving group
successfully provided the cyclization products 13a, 13b in
good yield. The studies on incorporation of the two fluorine-
containing amino acids into peptides are in progress.
Experimental
Compound 4 was prepared according to the literature pro-
cedures.32
In view of the failure of the cyclization of bromide 8b, we
envisioned that the mesylate as the leaving group should
probably afford the cyclization product (Scheme 4). Thus,
benzylation of the alcohol group of 5 yielded 9 in 95% yield.
Hydrolysis of the hemiaminal moiety of 9 with 80% AcOH
at 50 ЊC for 24 h afforded the alcohol 10 in 77% yield. The
alcohol group of 10 was protected as the tert-butyldimethylsilyl
(TBDMS) ether to give 11 in 87% yield and fortunately the two
diastereoisomers could be separated by flash chromatography
(hexane–ethyl acetate 50 : 1, 20 : 1, then 5 : 1). The hydro-
2-Trifluoromethyl-3-[(4R)-N-[(1,1-dimethyl)ethoxycarbonyl]-
2,2-dimethyl-1,3-oxazolidin-4-yl]propanol (5)
To a solution of 4 (2.75 g, 7.49 mmol) in MeOH (260 ml) was
added Raney-Ni (8 g, 50% w/w slurry in water, 50% mol). The
mixture was hydrogenated at room temperature overnight and
filtered through a pad of Celite, and the solvent was removed
in vacuo. The residue was taken up in Et2O (3 × 100 ml) and
the combined organic phase was washed with H2O and brine.
J. Chem. Soc., Perkin Trans. 1, 2002, 2052–2057
2053

View Article Online
Scheme 4
After the organic phase was dried over anhydrous Na2SO4 and
(2R)-2-[N-(1,1-Dimethyl)ethoxycarbonylamino]-5-bromo-4-tri-
filtered, the solvent was removed in vacuo to afford an oil which
was used without further purification. To a cooled solution of
LAH (0.76 g, 20 mmol) in 100 ml ether, the oil obtained above
in 100 ml ether was added slowly. The mixture was stirred at
0 ЊC until the reaction was shown to be complete by TLC and
the reaction was quenched by addition of 50 ml water. The
mixture was filtered and the filtrate was extracted with ether
(3 × 200 ml). The combined organic phases were washed with
brine and dried over anhydrous Na2SO4. After removal of the
solvent in vacuo, the residue was purified by flash chroma-
tography (hexane–ethyl acetate, 10 : 1) to give 5 as a white solid
fluoromethylpentanol (7)
A solution of 6 (500 mg, 1.28 mmol) in 80% AcOH was stirred
overnight at 50 ЊC, then the solvent was removed in vacuo and
the residue was diluted with Et2O (30 ml) and H2O (20 ml). The
aqueous phase was extracted with Et2O (3 × 20 ml) and the
combined organic phases were washed with saturated aqueous
NaHCO3 (20 ml) and brine and dried over anhydrous Na2SO4.
After removal of the solvent, the residue was purified by flash
chromatography (hexane–ethyl acetate, 10 : 1 then 5 : 1) to give
7a (less polar, 153.5 mg, 34%) as a white solid and 7b (more
polar, 181.4 mg, 40%) as a white solid. 7a mp = 72–74 ЊC; [α]2D0
=
1
(2.30 g, 94%). Mp = 47–49 ЊC; H NMR (CDCl3, 300 MHz)
1
ϩ34.8 (c 0.53, CHCl3); H NMR (CDCl3, 300 MHz) δ 1.44
(s, 9H), 1.85–1.94 (m, 2H), 2.05 (br s, 1H), 2.59–2.62 (m, 1H),
3.59–3.66 (m, 2H), 3.73–3.81 (m, 3H), 4.79–4.82 (d, J = 9 Hz,
1H); 19F NMR (CDCl3, 282 MHz) δ Ϫ70.8 (d, J = 9.9 Hz); IR
(KBr) 3338, 3256, 3072, 2976, 1670, 1558, 1175 cmϪ1; EI-MS
m/z 352 (Mϩ ϩ 2, <1%), 351 (Mϩ ϩ 1, <1), 350 (Mϩ, <1), 349
(Mϩ Ϫ 1, <1), 252 (6), 250 (6), 57 (100); Anal. Calcd for
C11H19F3NO3Br: C, 37.71; H, 5.44; N, 4.01. Found: C, 38.10;
H, 5.62; N, 3.87%. 7b mp = 102–104 ЊC [α]2D0 = ϩ13.0 (c 0.26,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.46 (s, 9H), 1.89–1.94
(m, 2H), 2.70–2.74 (br s, 1H), 3.34–3.40 (dd, J = 7.2, 7.8 Hz,
1H), 3.58–3.63 (dd, J = 3.3, 3.3 Hz, 1H), 3.70–3.73 (m, 2H),
3.81–3.82 (m, 1H), 4.82–4.85 (d, J = 7.2 Hz, 1H); 19F NMR
(CDCl3, 282 MHz) δ Ϫ71.2 (d, J = 8.7 Hz); IR (KBr) 3370,
2977, 1681, 1529, 1170 cmϪ1; EI-MS m/z 352 (Mϩ ϩ 2, <1%),
351 ( Mϩ ϩ 1, <1), 350 (Mϩ, <1), 349 (Mϩ Ϫ 1, <1), 252 (6), 250
(6), 57 (100); Found: C, 38.10; H, 5.63; N, 3.85. C11H19F3NO3Br
requires C, 37.71; H, 5.44; N, 4.01%.
δ 1.45–1.49 (m, 12H), 1.57–1.63 (m, 3H), 1.83–2.19 (m, 3H),
3.72–3.75 (m, 2H), 3.96–4.01 (dd, J = 4.8, 5.1 Hz, 2H), 4.27–
4.29 (br s, 1H); 19F NMR(CDCl3, 282 MHz) δ Ϫ69.7 (d, J =
9.3 Hz), Ϫ70.8 (d, J = 9.3 Hz); IR (KBr) 3473, 2983, 1690 cmϪ1
;
EI-MS m/z 312 (Mϩ Ϫ15, 5%), 212 (52), 57 (100); Found: C,
51.33; H, 7.44; N, 4.17. C14H24F3NO4 requires C, 51.38; H, 7.34;
N, 4.28%.
1-Bromo-2-trifluoromethyl-3-[(4R)-N-[(1,1-dimethyl)ethoxy-
carbonyl]-2,2-dimethyl-1,3-oxazolidin-4-yl]propane (6)
To CBr4 (5.80 g, 17.5 mmol) and Ph3P (4.80 g, 18.3 mmol), 5
(2.30 g, 7 mmol) in THF (70 ml) was added slowly, followed
by Er3N (5 ml, 35 mmol). The mixture was stirred at room
temperature overnight. The resulted red solution was diluted
with Et2O (100 ml) and H3PO4 (0.167 M, 50 ml). The aqueous
layer was extracted with Et2O (3 × 100 ml) and the combined
organic phases were washed with saturated aqueous Na2CO3
(2 × 50 ml) and brine and dried over anhydrous Na2SO4. After
removal of the solvent in vacuo, the residue was purified by flash
chromatography (hexane–ethyl acetate, 15 : 1) to give 6 as a
clear oil (2.59 g, 95%). 1H NMR (CDCl3, 300 MHz) δ 1.41–1.48
(m, 12H), 1.56–1.61 (m, 3H), 1.89–2.07 (m, 2H), 2.60, 2.76 (2 br
s, 1H), 3.34–3.45 (m, 1H), 3.53–3.58 (dd, J = 4.5, 4.2 Hz, 1H),
3.72–3.75 (d, J = 9.0 Hz, 1H), 3.97–4.02 (dd, J = 5.4, 4.5 Hz,
1H), 4.13 (br s, 1H); 19F NMR (CDCl3, 282 MHz) δ Ϫ70.5 (d,
J = 9 Hz), Ϫ70.8 (d, J = 9 Hz); IR (thin film) 2966, 1701, 1390,
1099 cmϪ1; EI-MS m/z 392 (Mϩ ϩ 2, 6%), 391 (Mϩ ϩ 1, 5), 390
(Mϩ, 6) 389 (Mϩ Ϫ1, 5), 292 (50), 292 (56), 57 (100); Found:
C, 42.64; H, 6.03; N, 3.30. C14H23F3NO3Br requires C, 43.07; H,
5.90; N, 3.59%.
(2R)-2-[N-(1,1-Dimethyl)ethoxycarbonylamino]-1-benzoyloxy-
5-bromo-4-trifluoromethylpentane (8b)
To a solution of 7b (206 mg, 0.59 mmol) in dry Et3N (6 ml),
benzoyl chloride (68µl, 0.59 mmol) was added dropwise. The
mixture was stirred at room temperature for 2 h and the solvent
was removed in vacuo. The residue was diluted with Et2O
(60 ml) and the organic phase was washed with 5% aqueous
NaHCO3 (2 × 10 ml), 3% aqueous hydrogen chloride (2 ×
10 ml), and brine and dried over anhydrous Na2SO4. After
removal of the solvent, the residue was purified by flash
chromatography (hexane–ethyl acetate, 15 : 1) to give 8b as a
white solid (219 mg, 82%). Mp = 104.5–106.5 ЊC; [α]2D0 = ϩ30.1
2054
J. Chem. Soc., Perkin Trans. 1, 2002, 2052–2057

View Article Online
1
(c 0.53, CHCl3); H NMR (CDCl3, 300 MHz) δ 1.43 (s, 9H),
to give 11a (less polar, 1.41 g, 37%) as a clear oil and 11b (more
1.94–2.03 (m, 2H), 2.75–2.80 (m, 1H), 3.34–3.40 (dd, J = 10.5,
8.7 Hz, 1H), 3.62–3.67 (dd, J = 3.6, 3.9 Hz, 1H), 4.18–4.22 (m,
1H), 4.34–4.36 (d, J = 4.5 Hz, 2H), 4.69–4.72 (d, J = 9 Hz, 1H),
7.44–7.50 (t, J = 7.8 Hz, 2H), 7.60–7.62 (t, J = 7.8 Hz, 1H),
8.03–8.06 (d, J = 7.8 Hz, 2H); 19F NMR (CDCl3, 282 MHz)
δ Ϫ70 (d, J = 66 Hz); IR (KBr) 3362, 2982, 1720, 1711, 1679,
1605, 1531 cmϪ1; EI-MS m/z 252 (6%), 57 (100); ESI-MS
m/z 456.1 (Mϩ ϩ 2), 454.1 (Mϩ); Found: C, 48.00; H, 5.18; N,
3.02. C18H23F3NO4Br requires C, 47.58; H, 5.07; N, 3.08%.
polar, 1.88 g, 50%) as a clear oil. 11a [α]2D0 = ϩ39.7 (c 0.80,
CHCl3); 1H NMR (CDCl3, 300 MHz) δ 0.05 (s, 6H), 0.89
(s, 9H), 1.43 (s, 9H), 1.76–1.83 (m, 2H), 2.43–2.45 (m, 1H),
3.53–3.58 (dd, J = 3.3, 3.3 Hz, 1H), 3.61–3.69 (m, 2H), 3.73–
3.77 (dd, J = 4.2, 4.8 Hz, 2H), 4.54 (s, 2H), 4.68–4.71 (d, J =
9.3 Hz, 1H), 7.30–7.40 (m, 5H); 19F NMR (CDCl3, 282 MHz)
δ Ϫ69.9 (d, J = 8.7 Hz); IR (thin film) 3363, 2951, 1716, 1499,
1455 cmϪ1; EI-MS m/z 493 (Mϩ ϩ 2, <1%), 492 (Mϩ ϩ 1, <1),
393 (11), 392 (13), 91 (100), 57 (32); Anal. Calcd for C24H40-
F3NO4Si: C, 58.66; H, 8.15; N, 2.85. Found: C, 58.88; H, 7.92;
N, 2.84%. 11b [α]2D0 = ϩ17.7 (c 0.75, CHCl3); 1H NMR (CDCl3,
300 MHz) δ 0.04 (s, 6H), 0.90 (s, 9H), 1.44 (s, 9H), 1.64–1.95
(m, 2H), 2.48–2.51 (m, 1H), 3.51–3.74 (m, 5H), 4.53 (s, 2H),
4.80–4.82 (d, J = 7.8 Hz, 1H), 7.31–7.38 (m, 5H); 19F NMR
(CDCl3, 282 MHz) δ Ϫ70.3 (d, J = 8.2 Hz); IR (thin film) 3449,
3067, 3033, 1716, 1499, 1455 cmϪ1; EI-MS m/z 493 (Mϩ ϩ 2,
<1%), 492 (Mϩ ϩ 1, <1), 392 (4), 91 (100), 57 (19); Found:
C, 58.90; H, 7.87; N, 2.82. C24H40F3NO4Si requires C, 58.66;
H, 8.15; N, 2.85%.
1-Benzyloxy-2-trifluoromethyl-3-[(4R)-N-[(1,1-dimethyl)ethoxy-
carbonyl]-2,2-dimethyl-1,3-oxazolidin-4-yl]propane (9)
A mixture of Bu4NI (750 mg, 2.03 mmol) and NaH (950 mg,
60% in oil, 23.75 mmol) was cooled to 0 ЊC and 5 (4.95 g, 15.13
mmol) in THF (60 ml) was added dropwise. The mixture was
stirred for 10 min at 0 ЊC and then stirred at room temperature
for 10 min. The mixture was cooled to 0 ЊC again and benzyl
bromide (2 ml, 16.78 mmol) was added dropwise and the
mixture was stirred at room temperature for 5 h. The reaction
was quenched with H2O (20 ml) and the mixture was extracted
with Et2O (3 × 100 ml). The combined organic phases were
washed with brine and dried over anhydrous Na2SO4. After
removal of the solvent in vacuo, the residue was purified by flash
chromatography (hexane–ethyl acetate, 100 : 1) to give 9 as a
(2S,4R)-4-[N-(1,1-Dimethyl)ethoxycarbonylamino]-5-tert-
butyldimethylsiloxy-2-trifluoromethylpentanol (12a)
To a solution of 11a (1.41 g, 2.86 mmol) in ethanol (80 ml),
Pd/C (10% Pd, 150 mg) was added. The mixture was hydro-
genated overnight at room temperature and filtered through a
pad of Celite, and the solvent was removed in vacuo. The
residue was purified by flash chromatography (hexane–ethyl
1
clear oil (5.97 g, 95%). H NMR (CDCl3, 300 MHz) δ 1.44
(s, 9H), 1.55–1.61 (m, 6H), 1.82–2.05 (m, 2H), 2.41 (br s, 1H),
3.46–3.80 (m, 3H), 3.92–3.97 (dd, J = 6.6, 5.4 Hz, 1H), 4.08–
4.10 (br s, 1H), 4.53–4.55 (m, 2H), 7.27–7.38 (m, 5H); 19F NMR
(CDCl3, 282 MHz) δ Ϫ69.2 (d, J = 8.7 Hz), Ϫ70.4 (d, J =
9.6 Hz); IR (thin film) 2982, 1699, 1497, 1480, 1173 cmϪ1; EI-
MS m/z 402 (Mϩ Ϫ 15, 2%), 302 (29), 91 (100), 57 (65); Found:
C, 60.42; H, 7.20; N, 3.38. C21H30F3NO4 requires C, 60.43; H,
7.19; N, 3.36%.
acetate, 5 : 1) to give 12a as a clear oil (1.14 g, 99%). [α]2D0
=
1
ϩ22.0 (c 0.71, CHCl3); H NMR (CDCl3, 300 MHz) δ 0.07 (s,
6H), 0.91 (s, 9H), 1.45 (s, 9H), 1.66–1.85 (m, 2H), 2.30 (br s,
1H), 3.57–3.61 (dd, J = 2.7, 3.0 Hz, 1H), 3.67–3.72 (dd, J = 3.6,
3.6 Hz, 1H), 3.78–3.99 (m, 3H), 4.86–4.89 (d, J = 9.6 Hz, 1H);
19F NMR (CDCl3, 282 MHz) δ Ϫ70.5 (d, J = 8.7 Hz); IR (thin
film) 3447, 3357, 1694, 1505, 1256, 1171, 1124 cmϪ1; EI-MS
m/z 302 (Mϩ Ϫ Boc, 20%), 57 (100); Found: C, 51.26; H, 8.40;
N, 3.51. C17H34F3NO4Si requires C, 50.87; H, 8.48; N, 3.49%.
(2R)-2-[N-(1,1-Dimethyl)ethoxycarbonylamino]-5-benzyloxy-
4-trifluoromethylpentanol (10)
The solution of 9 (920 mg, 2.21 mmol) in 80% AcOH (26 ml)
was stirred overnight at 50 ЊC. The solvent was removed in
vacuo and the residue was diluted with ethyl acetate (40 ml).
The organic phase was washed with saturated aqueous
NaHCO3 (2 × 30 ml) and brine and dried over anhydrous
NaSO4. After removal of the solvent in vacuo, the residue was
purified by flash chromatography (hexane–ethyl acetate, 5 : 1)
(2R,4R)-4-[N-(1,1-Dimethyl)ethoxycarbonylamino]-5-tert-
butyldimethylsiloxy-2-trifluoromethylpentanol (12b)
Compound 12b (1.40 g, 91%) was prepared as a clear oil from
compound 11b (1.88 g, 3.82 mmol) using the same conditions
as for compound 12a. [α]2D0 = ϩ10.5 (c 0.44, CHCl3); H NMR
1
(CDCl3, 300 MHz) δ 0.10 (s, 6H), 0.90 (s, 9H), 1.52 (s, 9H),
1.73–1.99 (m, 2H), 2.23–2.26 (br s, 1H), 3.60–3.72 (m, 3H),
3.72–3.86 (dd, J = 5.7, 5.7 Hz, 1H), 3.91–3.95 (dd, J = 4.5, 4.5
Hz, 1H), 4.96–5.00 (d, J = 6 Hz, 1H); 19F NMR (CDCl3, 282
MHz) δ Ϫ70.6 (d, J = 9.3 Hz); IR (thin film) 3447, 3357, 1694,
1505, 1256, 1171, 1124 cmϪ1; EI-MS m/z 302 (Mϩ Ϫ Boc, 20%),
57 (100); Found: C, 51.26; H, 8.40; N, 3.51. C17H34F3NO4Si
requires C, 50.87; H, 8.48; N, 3.49%.
1
to give 10 as a clear oil (645 mg, 77%). H NMR (CDCl3,
300 MHz) δ 1.44 (s, 9H), 1.65–1.98 (m, 2H), 2.28 (br s, 1H), 2.56
(m, 1H), 3.48–3.58 (m, 1H), 3.60–3.65 (m, 2H), 3.68–3.77 (m,
2H), 4.50–4.59 (m, 2H), 4.85, 5.07 (2 br s, 1H), 7.27–7.38 (m,
5H); 19F NMR (CDCl3, 282 MHz) δ Ϫ70.1 (d, J = 9.3 Hz),
Ϫ70.4 (d, J = 5.6 Hz); IR (thin film) 3423, 2979, 1692, 1509,
1456, 1170 cmϪ1; EI-MS m/z 347 (Mϩ Ϫ 30, <1%), 91 (100), 57
(76); C, 57.57; H, 7.05; N, 3.71. C18H26F3NO4 requires C, 57.29;
H, 6.90; N, 3.71%.
(2R,4S )-2-(tert-Butyldimethylsilyloxymethyl)-4-trifluoromethyl-
N-[(1,1-dimethyl)ethoxycarbonyl]pyrrolidine (13a)
(2R,4S )-2-[N-(1,1-Dimethyl)ethoxycarbonylamino]-1-tert-
butyldimethylsilyloxy-5-benzyloxy-4-trifluoromethylpentane
(11a), and (2R,4R)-2-[N-(1,1-dimethyl)ethoxycarbonylamino]-
1-tert-butyldimethylsilyloxy-5-benzyloxy-4-trifluoromethyl-
pentane (11b)
A mixture of 12a (1.14 g, 2.84 mmol), methanesulfonyl chloride
(4 ml, 51.68 mmol) and Et3N (15 ml, 107.9 mmol) in CH2Cl2
(30 ml) was stirred overnight at room temperature. After dilu-
tion with H2O, the aqueous layer was extracted with CH2Cl2
(3 × 40 ml) and the combined organic phases were washed
with saturated aqueous NaHCO3, H2O and brine and dried
over anhydrous Na2SO4. After removal of the solvent, the resi-
due was treated with KHMDS (3.0 ml, 20% in toluene) in THF
(200 ml) at 0 ЊC for 24 h. The reaction was quenched with
saturated aqueous NH4Cl (40 ml) and the aqueous layer was
extracted with Et2O (3 × 50 ml). The combined organic phases
were washed with H2O (50 ml), brine and dried over anhydrous
Na2SO4. After removal of the solvent, the residue was purified
by flash chromatography (hexane–ethyl acetate, 100 : 1) to give
To a solution of 10 (2.89 g, 7.67 mmol) and imidazole (2.00 g,
29.40 mmol) in CH2Cl2 (80 ml), TBDMSCl (2.10 g, 13.93
mmol) in CH2Cl2 (40 ml) was added dropwise. After the mix-
ture was stirred at room temperature for 1 h, the reaction was
quenched with H2O (40 ml). The aqueous layer was extracted
with CH2Cl2 (3 × 100 ml) and the combined organic phases
were washed with brine and dried over anhydrous Na2SO4.
After removal of the solvent, the residue was purified by flash
chromatography (hexane–ethyl acetate, 50 : 1, 20 : 1, then 5 : 1)
J. Chem. Soc., Perkin Trans. 1, 2002, 2052–2057
2055

View Article Online
13a (904 mg, 83%) as a clear oil. [α]2D0 = ϩ40.8 (c 1.93, CHCl3);
1H NMR (CDCl3, 300 MHz) δ 0.03 (s, 6H), 0.88 (s, 9H), 1.45
(s, 9H), 2.05–2.15 (m, 2H), 3.08–3.22 (m, 1H), 3.37–3.68 (m,
3H), 3.86–3.90 (dd, J = 3.6, 3.3 Hz, 1H), 4.00–4.01 (br s, 1H);
19F NMR (CDCl3, 282 MHz) δ Ϫ72.6 (t, J = 8.6 Hz); IR (thin
film) 2961, 1704, 1473, 1391, 1262, 1137 cmϪ1; EI-MS m/z 384
(Mϩ ϩ 1, 15%), 284 (100), 57 (66); ESI-HRMS m/z 406.1996
(Mϩ ϩ Na, C17H32F3NO3NaSi requires 406.1933); Found:
C, 53.27; H, 8.28; N, 4.07. C17H32F3NO3Si requires C, 53.26;
H, 8.36; N, 3.66%.
anhydrous Na2SO4. After removal of the solvent, the residue
was purified by flash chromatography (hexane–ethyl acetate
5 : 1 then 0 : 100) to give 15a (130 mg, 56%) as a white solid.
Mp = 113–115 ЊC; [α]2D0 = ϩ70.0 (c 0.45, CHCl3); H NMR
1
(CDCl3, 300 MHz) δ 1.38, 1.44 (2s, 9H), 2.19–2.30 (m, 1H),
2.35–2.47 (m, 1H), 2.97–3.08 (m, 1H), 3.43–3.57 (m, 1H), 3.64–
3.77 (2× dd, J = 8.7, 8.4, 8.4, 9.0 Hz, 1H), 4.34–4.47 (2 × dd,
J = 2.7, 2.4, 2.4, 2.7 Hz, 1H), 8.38–8.51 (m, 1H); 19F NMR
(CDCl3, 282 MHz) δ Ϫ72.4 (d, J = 36.7 Hz); IR (KBr) 3000–
2500, 1759, 1673, 1399, 1144 cmϪ1; EI-MS m/z 239 (Mϩ Ϫ 44,
3%), 138 (94), 57 (100); Found: C, 46.71; H, 5.74; N, 4.94.
C11H16F3NO4 requires C, 46.64; H, 5.65; N, 4.95%.
(2R,4R)-2-(tert-Butyldimethylsilyloxymethyl)-4-trifluoromethyl-
N-[(1,1-dimethyl)ethoxycarbonyl]pyrrolidine (13b)
(2R,4R)-N-[(1,1-Dimethyl)ethoxycarbonyl]-4-trifluoromethyl-
D-proline (15b)
Compound 13b (1.07 g, 80%) was prepared as a clear oil from
compound 12b (1.40 g, 3.49 mmol) using the same conditions
as for compound 13a. [α]2D0 = ϩ58.0 (c 1.21, CHCl3); H NMR
1
Compound 15b (258 mg, 68%) was prepared as a white solid
from compound 14b (360 mg, 1.34 mmol) using the same con-
ditions as for compound 15a. Mp = 124–126 ЊC, [α]2D0 = ϩ79.0
(CDCl3, 300 MHz) δ 0.05 (s, 6H), 0.88 (s, 9H), 1.46 (s, 9H),
2.20–2.25 (m, 2H), 2.76–2.84 (m, 1H), 3.19–3.26 (t, J = 10.2 Hz,
1H), 3.62–3.97 (m, 4H); 19F NMR (CDCl3, 282 MHz) δ Ϫ71.6
1
(c 0.98, CHCl3); H NMR (CDCl3, 300 MHz) δ 1.44, 1.50 (2s,
(t, J = 7.0 Hz); IR (thin film) 2957, 1702, 1474, 1392, 1167 cmϪ1
;
9H), 2.19–2.42 (m, 1H), 2.54–2.64 (m, 1H), 2.94–3.02 (m, 1H),
3.47–3.52 (m, 1H), 3.83–3.97 (m, 1H), 4.34–4.48 (dt, J = 28.8,
7.6 Hz, 1H), 8.87 (br s, 1H); 13C NMR (CDCl3, 75.5 MHz)
δ 177.3, 175.7, 154.6, 153.4, 127.6, 123.9, 81.7, 81.4, 58.3, 58.2,
45.9, 45.6, 41.8, 41.5, 41.2, 40.8, 29.9, 28.6, 28.2, 28.0;19F NMR
(CDCl3, 282 MHz) δ Ϫ71.0 (d, J = 7.05 Hz); IR (KBr) 3000–
2500, 1750, 1648, 1440, 1182 cmϪ1; EI-MS m/z 238 (Mϩ Ϫ 45,
4%), 138 (38), 57 (100); Found: C, 46.66; H, 5.74; N, 4.81.
C11H16F3NO4 requires C, 46.64; H, 5.65; N, 4.95%.
EI-MS m/z 385 (Mϩ ϩ 2, 5%), 384 (Mϩ ϩ 1, 4) 271 (100), 57
(66); Found: C, 53.39; H, 8.16; N, 3.65. C17H32F3NO3Si requires
C, 53.26; H, 8.36; N, 3.66%.
(2R,4S )-2-Hydroxymethyl-4-trifluoromethyl-N-[(1,1-dimethyl)-
ethoxycarbonyl]pyrrolidine (14a)
To a cooled solution of 13a (395 mg, 1.03 mmol) in THF (10 ml),
TBAF (1.1 ml, 1.1 M in THF, 1.1 mmol) was added dropwise.
The mixture was stirred at room temperature for 2 h. The
reaction was quenched with H2O (5 ml) and Et2O (20 ml) was
added. The aqueous layer was extracted with Et2O (3 × 20 ml)
and the combined organic phases were washed with brine and
dried over anhydrous Na2SO4. After removal of the solvent, the
residue was purified by flash chromatography (hexane–ethyl
acetate 10 : 1 then 5 : 1) to give 14a (280 mg, 100%) as a clear
oil. [α]2D0 = ϩ26.8 (c 1.47, CHCl3); 1H NMR (CDCl3, 300 MHz)
δ 1.45 (s, 9H), 1.94–2.01 (br s, 1H), 2.16–2.27 (m, 1H), 2.97–3.06
(br s, 1H), 2.97–3.05 (m, 1H), 3.57–3.63 (m, 3H), 3.70–3.75 (dd,
J = 3.3, 3.9 Hz, 1H), 4.09–4.10 (br s, 1H); 19F NMR (CDCl3,
282 MHz) δ Ϫ72.7 (d, J = 7 Hz); IR (thin film) 3437, 2980, 1699,
1678, 1480, 1134 cmϪ1; EI-MS m/z 238 (Mϩ Ϫ 31, 8%), 138 (34),
57 (100); Found: C, 49.33; H, 7.14; N, 5.08. C11H18F3NO3
requires C, 49.07; H, 6.69; N, 5.20%.
References
1 R. P. Kukhá and V. A. Soloshonok, Fluorine-containing Amino
Acids, Wiley & Sons, New York, 1997.
2 (a) D. B. Harper and D. O’Hagan, Nat. Prod. Rep., 1994, 11, 123; (b)
B. E. Smart. in Molecular Structure and Energetics, ed. J. L. Liebman
and A. Greenberg, VCH Publishers Inc., Deerfield Park, Florida,
1986, vol. 3, p. 141.
3 (a) S. M. Hecht, Acc. Chem. Res., 1992, 25, 545; (b) V. W. Cornish,
D. Mende and P. G. Schultz, Angew. Chew. Int. Ed. Engl., 1995, 34,
621; (c) D. R. Liu, T. J. Magliery, M. Pastrnak and P. G. Schultz,
Proc. Natl. Acad. Sci. USA, 1997, 94, 10092; (d ) R. Furter, Protein
Sci., 1998, 7, 419; (e) D. R. Liu and P. G. Schultz, Proc. Natl. Acad.
Sci. USA, 1999, 96, 4780.
4 J. T. Welch and S. Eswarakrishnan, Fluorine in Bioorganic Chemistry,
Wiley, New York, 1991.
5 (a) C. T. Walsh, Annu. Rer. Biochem., 1984, 53, 493; (b) R. Filler,
Y. Kobayashi and L. M. Yagupolskii, Biomedical Aspects of Fluorine
Chemistry, Elsevier, Amsterdam, 1993, p. 241.
6 (a) A. Niemz and D. A. Tirrell, J. Am. Chem. Soc., 2001, 123, 7407;
(b) Y. Tang, G. Ghirlanda, W. Petka, T. Nakajima, W. Degrado and
D. A. Tirrell, Angew. Chem., Int. Ed., 2001, 40, 1494.
7 (a) B. Bilgiçer, A. Fichera and K. Kumar, J. Am. Chem. Soc., 2001,
123, 4393; (b) B. Bilgiçer, X. Xing and K. Kumar, J. Am. Chem. Soc.,
2001, 123, 11815.
8 Fluorine-containing Amino Acids, Synthesis and Properties, ed.
V. P. Kukhar’ and V. A. Soloshonok, Wiley, Chichester, 1995.
9 A. Sutherland and C. L. Willis, Nat. Prod. Rep., 2000, 17, 621.
10 For recent examples, see: (a) D. W. Konas and J. K. Coward, J. Org.
Chem., 2001, 66, 8831; (b) X. Xing, A. Fichera and K. Kumar, Org.
Lett., 2001, 3, 1285; (c) S. Fustero, A. Navarro, B. Pina, J. G. Soler,
A. Bartolomé, A. Asensio, A. Simón, P. Bravo, G. Fronza,
A. Volonterio and M. Zanda, Org. Lett., 2001, 3, 2621; (d ) H. Abe,
H. Amii and K. Uneyama, Org. Lett., 2001, 3, 313; (e) N. Lebouvier,
C. Laroche, F. Huguenot and T. Brigaud, Tetrahedron Lett., 2002,
43, 2827; ( f ) X. Xing, A. Fichera and K. Kumar, J. Org. Chem.,
2002, 67, 1722.
(2R,4R)-2-Hydroxymethyl-4-trifluoromethyl-N-[(1,1-dimethyl)-
ethoxycarbonyl]pyrrolidine (14b)
Compound 14b (600 mg, 100%) was prepared as a clear oil from
compound 13b (857 mg, 2.23 mmol) using the same conditions
as for compound 14a. [α]2D0 = ϩ43.8 (c 0.99, CHCl3); H NMR
1
(CDCl3, 300 MHz) δ 1.48 (s, 9H), 1.65–1.71 (m, 1H), 2.25–2.34
(m, 1H), 2.81–2.90 (m, 1H), 3.30–3.37 (t, J = 10.8 Hz, 1H),
3.62–3.71 (m, 2H), 3.75–3.84 (m, 1H), 3.97–4.05 (m, 1H); 19F
NMR (CDCl3, 282 MHz) δ Ϫ71.9 (d, J = 4.8 Hz); IR (thin film)
3427, 2981, 1697, 1679, 1396, 1137 cmϪ1; EI-MS m/z 271 (Mϩ ϩ
2, 5%), 270 (Mϩ ϩ 1, 5), 238 (Mϩ Ϫ 31, 2), 57 (100); Found:
C, 49.30; H, 7.14; N, 5.10. C11H18F3NO3 requires C, 49.07; H,
6.69; N, 5.20%.
(2R,4S )-N-[(1,1-Dimethyl)ethoxycarbonyl]-4-trifluoromethyl-
D-proline (15a)
To a 0 ЊC solution of 14a (220 mg, 0.82 mmol) in acetone (20 ml),
Jones reagent (10 ml) was added dropwise. The mixture was
stirred at 0 ЊC for 7 h. After the remaining oxidant was
decomposed by the addition of propan-2-ol (5 ml), the solvent
was removed in vacuo and the residue was diluted with ether
and water. The organic layer was separated and the aqueous
phase was extracted with ether (3 × 30 ml). The combined
organic phases were washed with brine and dried over
11 M. Nevalainen, P. M. Kauppinen and A. M. P. Koskinen, J. Org.
Chem., 2001, 66, 2061.
12 M. Tamaki, T. Okitsu, M. Araki, H. Sakamoto, M. Takimoto and
I. Muramastu, Bull. Chem. Soc. Jpn., 1985, 58, 531.
13 M. A. Ondetti, B. Rubin and D. W. Cushman, Science, 1977, 196,
441.
14 A. A. Patchett, E. Harris, E. W. Tristram, M. J. Wyvratt, M. T. Wu,
D. Taub, E. R. Peterson, T. J. Ikeler, J. T. Broeke, L. G. Payne,
D. L. Ondeyka, E. D. Thorsett, W. J. Greenlee, N. S. Lohr,
2056
J. Chem. Soc., Perkin Trans. 1, 2002, 2052–2057

View Article Online
19 Our group recently prepared Boc-protected cis-4-trifluoromethyl--
R. D. Hoffsommer, H. Joshua, W. V. Ruyle, J. W. Rothrock,
S. D. Aster, A. L. Maycock, F. M. Robinson, R. Hirschmann,
C. S. Sweet, E. H. Ulm, D. M. Gross, T. C. Vassil and C. A. Stone,
Nature, 1980, 288, 280.
proline starting from 4-hydroxy--proline using the methodology
being similar to Goodman’s. X. L. Qui and F. L. Qing, J. Org.
Chem., 2002, in the press.
15 (a) N. A. Sasaki, M. Dockner, A. Chiaroni, C. Riche and P. Potier,
J. Org. Chem., 1997, 62, 765; (b) M. Dockner, N. A. Sasaki and
P. Potier, Heterocycles, 1996, 42, 529; (c) M. Tamaki, G. Han and
V. J. Hruby, J. Org. Chem., 2001, 66, 3593.
20 X. Zhang, F.-L. Qing, Y. Yang, J. Yu and X.-K. Fu, Tetrahedron
Lett., 2000, 41, 2953.
21 Q.-Y. Chen and S.-W. Wu, J. Chem. Soc., Chem. Commun., 1989, 705.
22 D. B. Denney and S. T. Ross, J. Org. Chem., 1962, 27, 998.
23 (a) P. Garner and J. M. Park, J. Org. Chem., 1987, 52, 2361;
(b) P. Garner and J. M. Park, Org. Synth., 1992, 70, 18.
24 (a) T. Kitazume, T. Ohnogi, H. Miyauchi and T. Yamazaki,
J. Org. Chem., 1989, 54, 5603; (b) T. Yamazaki, S. Hiraoka and
T. Kitazume, J. Org. Chem., 1994, 59, 5100.
25 I. Kadota, S. Saya and Y. Yamamoto, Heterocycles, 1997, 46, 335.
26 (a) S. Watanabe and Y. Sakai, J. Fluorine Chem., 1994, 67, 149;
(b) T. Konno, H. Nakano and T. Kitazume, J. Fluorine Chem., 1997,
86, 81; (c) T. Konno, H. Umetani and T. Kitazume, J. Org. Chem.,
1997, 62, 137.
27 (a) W. A. Szarek, A. Zamojski, K. N. Tiwari and E. R. Ison,
Tetrahedron Lett., 1986, 27, 3827; (b) F.-L. Qing, S. Peng and
C.-M. Hu, J. Fluorine Chem., 1998, 88, 79.
28 X. Xing, A. Fichera and K. Kumar, Org. lett., 2001, 3, 1285.
29 A. M. P. Koskinen and L. A. Otsomaa, Tetrahedron, 1997, 53, 6473.
30 (a) N. Ikota, Heterocycles, 1995, 41, 983; (b) N. Ikota, H. Nakagawa,
S. Ohno, K. Noguchi and K. Okuyama, Tetrahedron, 1998, 54, 8985;
(c) M. Yokoyama, T. Ikenogami and H. Togo, J. Chem. Soc., Perkin
Trans. 1,, 2000, 2067.
16 (a) F. N. Shirota, H. T. Nagasawa and J. A. Elberling, J. Med. Chem.,
1977, 20, 1176; (b) A. Gottlieb, Y. Fujita, S. Underfriend and
B. Witkop, Biochemistry, 1965, 4, 2507; (c) E. M. Smith, G. F. Swiss,
B. R. Neustadt, E. H. Gold, J. A. Sommer, A. D. Brown, P. J. S.
Chiu, R. Moran, E. J. Sybertz and T. Baum, J. Med. Chem., 1988,
31, 875; (d ) M. Hudlický and J. S. Merola, Tetrahedron Lett., 1990,
31, 7403; (e) D. R. Kronenthal, R. H. Mueller, P. L. Kuester,
T. P. Kissick and E. J. Johnson, Tetrahedron Lett., 1990, 31, 1241;
( f ) A. G. Avent, A. N. Bowler, P. M. Doyle, C. M. Marchand and
D. W. Young, Tetrahedron Lett., 1992, 33, 1509; (g) M. Hudlický,
J. Fluorine Chem., 1993, 60, 193; (h) B. P. Hart and J. K. Coward,
Tetrahedron Lett., 1993, 34, 4917; (i) K. Burger, M. Rudolph,
S. Fehn and N. Sewald, J. Fluorine Chem., 1994, 66, 87; (j)
T. T. Tran, N. Patino, R. Condom, T. Frogier and R. Guedj,
J. Fluorine Chem., 1997, 82, 125; (k) M. Tandon, M. Wu and
T. P. Begley, Bioorg. Med. Chem. Lett., 1998, 8, 1139; (l )
L. Demange, A. Ménez and C. Dugave, Tetrahedron Lett., 1998, 39,
1169; (m) L. Demange, J. Cluzeau, A. Ménez and C. Dugave,
Tetrahedron Lett., 2001, 42, 651.
17 J. Leroy and C. Wakselman, Can. J. Chem., 1976, 54, 218.
18 During the preparation of this manuscript, Goodman et. al.
reported the stereoselective synthesis of cis and trans-4-trifluoro-
methyl--prolines by asymmetric hydrogenation. J. R. Del Valle and
M. Goodman, Angew. Chem., Int. Ed., 2002, 41, 1600.
31 (a) K. Bowden, I. M. Heilbron, E. R. H. Jones and B. C. L. Weedon,
J. Chem. Soc., 1946, 39; (b) A. Barco, S. Benetti, G. Spalluto,
A. Casolari, G. P. Pollini and V. Zanirato, J. Org. Chem., 1992, 57,
6279.
32 X. Zhang, F.-L. Qing and Y. Yu, J. Org. Chem., 2000, 65, 7075.
J. Chem. Soc., Perkin Trans. 1, 2002, 2052–2057
2057