Practical synthesis of Boc-protected cis-4-trifluoromethyl and cis-4-difluoromethyl-L- prolines

Article abstract of DOI:10.1021/jo0257400

A short, efficient, and diastereomerically pure synthesis of N-Boc-cis-4-trifluoromethyl-L-proline (7) and N-Boc-cis-4-difluoromethyl-L-proline (9) from N-Boc-4-oxo- L-proline (4) is described. The reaction of 4 with Me₃SiCF₃ and the conversion of the carbonyl group of 4 into the difluoromethylene group are the key steps for the synthesis of 7 and 9, respectively.

Full text of DOI:10.1021/jo0257400

SCHEME 1
P r a ctica l Syn th esis of Boc-P r otected
cis-4-Tr iflu or om eth yl a n d
cis-4-Diflu or om eth yl-L- p r olin es
Xiao-long Qiu† and Feng-ling Qing*,†,‡
Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China, and College of
Chemistry and Chemical Engineering, Donghua University,
1882 West Yanan Lu, Shanghai 200051, China
flq@pub.sioc.ac.cn
Received March 20, 2002
derivatives are a type of important amino acids in many
naturally occurring bioactive peptides such as gramici-
din,9 and have been extensively used in the pharmaceuti-
cal industry as angiotensin-converting enzyme (ACE)
inhibitors, including Captopril10 and Enalapril.11 Fluori-
nated prolines are useful tools for investigating protein-
peptide or protein-protein interactions as well as con-
formations.6 Recently, Luis Moroder et al. applied
4-fluoroproline as a tool for protein design and engineer-
ing.12 Among the fluorinated prolines, there are a number
of methods describing the preparation of 4-fluoro- and
4-difluoroprolines.13 However, to the best of our knowl-
edge, only one group reported the synthesis of racemic
methyl N-tert-butyl-4-trifluoromethyl prolinate via (2+3)
cycloaddition.14 Herein, we report a short, efficient, and
diastereomerically pure synthesis of N-Boc-cis-4-trifluo-
romethyl-L-proline (7) and N-Boc-cis-4-difluoromethyl-L-
proline (9) from a naturally abundant amino acid L-hy-
droxyproline (1).
N-Boc-4-oxo-L-proline (4) is a suitable intermediate for
the synthesis of fluorinated prolines 7 and 9. N-Boc-4-
oxo-L-proline (4) is derived from L-hydroxyproline (1) and
could be obtained through a slight modification of a
published procedure (Scheme 1).15 Initially, treatment of
1 with di-tert-butyl dicarbonate in the presence of 10%
aqueous NaOH provided N-tert-butoxycarbonyl-trans-4-
hydroxy-L-proline (2). The carboxyl group of 2 was
Abstr a ct: A short, efficient, and diastereomerically pure
synthesis of N-Boc-cis-4-trifluoromethyl-L-proline (7) and
N-Boc-cis-4-difluoromethyl-L-proline (9) from N-Boc-4-oxo-
L-proline (4) is described. The reaction of 4 with Me3SiCF3
and the conversion of the carbonyl group of 4 into the
difluoromethylene group are the key steps for the synthesis
of 7 and 9, respectively.
The substitution of fluorine for hydrogen within the
natural amino acids has been used as a powerful tool for
bioorganic and medicinal chemists. Fluorinated amino
acids and large molecules containing them have enjoyed
widespread popularity and been used in applications such
as biochemical probes, alternate enzyme substrates, and
enzyme inhibitors.1,2 Especially, incorporation of fluori-
nated amino acids provides a route to proteins and
peptides with unique structural and chemical features.3
For example, Tirrell4 and Kumar5 recently found that
fluorinated coiled-coil protein prepared from trifluoro-
leucine and trifluovaline displays enhanced thermal and
chemical stability. Therefore, there is a large body of
literature describing methods for the synthesis of fluori-
nated amino acids.6-8 Proline and its 4-substituted
† Chinese Academy of Sciences.
‡ Donghua University.
(1) Welch, J . T.; Eswarakrishnan, S. Fluorine in Bioorganic Chem-
istry; J ohn Wiley and Sons: New York, 1991.
(2) Organofluorine Compounds in Medicinal Chemistry and Bio-
medical Appliccations; Filler, R., Kobayashi, Y., Yagupolskii, L. M.,
Eds.; Elsevier: Amsterdam, 1993.
(3) (a) Hecht, S. M. Acc. Chem. Res. 1992, 25, 545. (b) Cornish. V.
W.; Mendel, D.; Schultz, P. G. Angew. Chem., Int. Ed. Engl. 1995, 34,
621. (c) Liu, D. R.; Magliery, T. J .; Pastrnak, M.; Schultz, P. G. Proc.
Natl. Acad. Sci. U.S.A. 1997, 94, 10092. (d) Furter, R. Protein Sci. 1998,
7, 419. (e) Liu, D. R.; Schultz, P. G. Proc. Natl. Acad. Sci. U.S.A. 1999,
96, 4780.
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Tirrell, D. A. Angew. Chem., Int. Ed. 2001, 40, 1494.
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123, 4393. (b) Bilgic¸er, B.; Xing, X.; Kumar, K. J . Am. Chem. Soc. 2001,
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L. G.; Ondeyka, D. L.; Thorsett, E. D.; Greenlee, W. J .; Lohr, N. S.;
Hoffsommer, R. D.; J oshua, H.; Ruyle, W. V.; Rothrock, J . W.; Aster,
S. D.; Maycock, A. L.; Robinson, F. M.; Hirschmann, R.; Sweet, C. S.;
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(b) Hudlicky´, M. J . Fluorine Chem. 1993, 60, 193. (c) Kronenthal, D.
R.; Mueller, R. H.; Kuester, P. L.; Kissick, T. P.; J ohnson, E. J .
Tetrahedron Lett. 1990, 31, 1241. (d) Gottlieb, A. A.; Fujita, Y.;
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10.1021/jo0257400 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002
7162
J . Org. Chem. 2002, 67, 7162-7164

SCHEME 2
F IGURE 1. NOE correlation from NOESY spectra of 7 and 9
SCHEME 3
protected in the form of benzyl ester 3, since the benzyl
ester group could be removed under hydrogenolysis. The
hydroxyl group of 3 was oxidized by chromium trioxide
and pyridine to give N-Boc-4-oxo-L-proline (4).
The nucleophilic trifluoromethylation reaction of the
carbonyl group with (trifluoromethyl)trimethylsilane (Me3-
SiCF3) is rapidly becoming the method for introduction
of a trifluoromethyl group into an organic compound.16
It was anticipated that the treatment of 4 with Me3SiCF3
would lead to an intermediate 5 that could be converted
to the target molecule 7. In fact, the reaction of 4 with
1.0 equiv of Me3SiCF3 in the presence of catalytic tet-
rabutylammonium fluoride (TBAF) at room temperature
overnight resulted in the total conversion of 4. However,
with the addition of TBAF to the reaction mixture for
the desilylation following the usual procedure, the ex-
pected product 5 was isolated in low yield, and the
byproducts were formed as indicated by the 19F NMR of
the reaction mixture. Fortunately, in the desilylation
step, the addition of saturated aqueous NH4Cl and
stirring for 15 min followed by the addition of TBAF
afforded 5 in 81% yield (Scheme 2). It seemed that
saturated aqueous NH4Cl could make the desilylation
mild and reduce the formations of byproducts. It was
necessary to add TBAF for total desilylation. Dehydration
of 5 with thionyl chloride in pyridine under reflux
provided trifluoromethylated olefin 6 in 78% yield.17
Hydrogenation and deprotection of 6 by hydrogen with
Pd/C led to a single diastereoisomer, N-Boc-cis-4-trifluo-
romethyl-L-proline (7) in 90% yield.18 Neither high-
resolution NMR nor HPLC was able to detect any of the
other diastereoisomer. The X-ray structure of compound
7 and NOESY experiment demonstrated that the tri-
fluoromethyl group is cis to the acid group (Figure 1).
hydrogenated to afford the desired product 9 in 64% yield,
which was confirmed as the single diasteroisomerby 19F
NMR and NOESY (Figure 1). To the best of our knowl-
edge, this is the first synthesis of N-Boc-cis-4-difluoro-
methyl-L-proline.
In summary, we have developed a short, efficient, and
diastereoisomerically pure synthesis of N-Boc-cis-4-
trifluoromethyl-L-proline (7) and N-Boc-cis-4-difluorom-
ethyl-L-proline (9) from a naturally abundant amino acid
L-hydroxyproline (1). The following points derived from
our synthesis are noteworthy: (1) the original material
is natural and cheap, (2) the synthetic route is short and
efficient, (3) the diastereomeric excess is very high
(almost optically pure), and (4) the preparation could be
scaled up to several grams. Studies detailing the incor-
poration of the two building blocks into peptides and
subsequent characterization are in progress.
Exp er im en ta l Section
N-ter t-Bu toxyca r bon yl-tr a n s-4-h yd r oxy-L-p r olin e (2). A
mixture of trans-4-hydroxy-L-proline (1, 25.0 g, 0.19 mol) in 380
mL of a 2:1 mixture of THF/H2O was treated first with 10%
aqueous NaOH (80 mL) and then with di-tert-butyldicarbonate
(60 g, 0.28 mol). The reaction mixture was stirred at room
temperature overnight and then the THF was removed in vacuo.
The residue was adjusted to pH 2 by the addition of 10% aqueous
KHSO4. The acidic solution was extracted several times with
ethyl acetate. The combined organic extracts were washed with
H2O and brine and then dried over anhydrous Na2SO4. Removal
of the desiccant and evaporation of the solvent in vacuo gave 2
(44.0 g, 100%) as a syrup, which was used without further
purification.
Ben zyl (2S,4R)-N-ter t-Bu toxyca r bon yl-4-h yd r oxyp r oli-
n a te (3). To a solution of 2 (10.0 g, 43.30 mmol) in anhydrous
THF (45 mL) was added dry Et3N (8 mL). The solution was
cooled to 0 °C and BnBr (7 mL, 58.50 mmol) in THF (5 mL) was
added dropwise. The reaction mixture was stirred at 0 °C for 5
min, then warmed to room temperature and stirred overnight.
The key step for the synthesis of N-Boc-cis-4-difluo-
romethyl-L-proline (9) was to convert the carbonyl group
of 4 into the difluoromethylene group. Treatment of 4
with dibromodifluoromethane/Zn/HMPT19 in THF gave
the key intermediate 8 in 48% yield (Scheme 3). 8 was
(16) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
(b) Singh, R. P.; Shreeve, J . M. Tetrahedron 2000, 56, 7613.
(17) (a) Gassman, P. G.; Ray, J . A.; Wenthold, P. G.; Mickelson, J .
W. J . Org. Chem. 1991, 56, 5143. (b) Kaneko, S.; Nakajima, N.;
Shikano, M.; Katoh, T.; Terashima, S. Tetrahedron, 1998, 54, 5485.
(18) During the examination of this paper, Goodman et al. reported
the stereoselective synthesis of 7. Del Valle, J . R.; Goodman, M. Angew.
Chem., Int. Ed. 2002, 41, 1600.
(19) (a) Motherwell, W. B.; Tozer, M. J .; Ross, B. C. Chem. Commun.
1989, 1437. (b) Houlton, J . S.; Motherwell, W. B.; Ross, B. C.; Tozer,
M. J .; Williams, D. J .; Slawin, A. M. Tetrahedron 1993, 49, 8087. (c)
Lim, M. H.; Kim, H. O.; Moon, H. R.; Chun, M. W.; J eong, L. S. Org.
Lett. 2002, 4, 529.
J . Org. Chem, Vol. 67, No. 20, 2002 7163

The solvent was removed in vacuo and the residue was dissolved
in CH2Cl2 (500 mL). The resultant organic phase was washed
with 1 N HCl (150 mL), H2O (150 mL), 5% aqueous Na2CO3 (150
mL), and H2O (50 mL) and dried over anhydrous Na2SO4. The
solvent was removed in vacuo and the crude product was purified
by flash chromatography (hexane/ethyl acetate, 2:1) to give 3
(6.17 g, 44%) as a clear oil. [R]20D -58.0 (c 1.24, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.35 (m, 5H), 5.16 (m, 2H), 4.51-4.41 (m,
2H), 3.66-3.58 (m, 2H), 2.31-2.28 (m, 1H), 2.11-2.05 (m, 1H),
for C18H20F3NO4: C, 58.22; H, 5.39; N, 3.77. Found: C, 58.43;
H,5.62; N, 3.98.
(2S ,4S )-N -t er t -B u t o x y c a r b o n y l-4-t r iflu o r o m e t h y l-
p r olin e (7). Pd/C (490 mg, 10%Pd) was added to a solution of 6
(394 mg, 1.39 mmol) in EtOH (25 mL), then the solution was
hydrogenated at room temperature overnight. After filtration
and removal of the solvent in vacuo, the residue was purified
by flash chromatography (hexane/ethyl acetate, 1:1) to give 7
(360 mg, 90%) as a white solid. Mp 124.5-126.5 °C; [R]20D -77.6
(c 0.70, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.98-8.91 (bs, 1H),
4.48-4.33 (dt, J ) 29, 7.8 Hz, 1H), 3.96-3.82 (m, 1H), 3.53-
3.45 (m, 1H), 3.04-2.90 (m, 1H), 2.67-2.53 (m, 1H), 2.41-2.19
(m, 1H), 1.49, 1.43 (2s, 9H); 19F NMR (282 MHz, CDCl3) δ -71.2
(d, J ) 4.8 Hz); 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; IR (thin film) 3000-2500,
1726, 1647, 1481, 1445, 1407, 1280, 1164, 699 cm-1; MS(EI) m/z
238 (M+ - COOH, 3), 182 (M+ - Boc, 23), 138 (M+ - Boc -
COOH, 37), 69 (2), 57 (100).; Anal. Calcd for C11H16F3NO4: C,
46.64; H, 5.65; N, 4.95. Found: C, 46.80; H, 5.65; N, 4.92.
Ben zyl (2S)-N-ter t-Bu t oxyca r b on yl-4-d iflu or om et h yl-
en ep r olin a te (8). CF2Br2 (0.30 mL, 3.06 mmol) and HMPT (0.67
mL, 3.06 mmol) were added at 0 °C to a solution of 4 (229 mg,
0.72 mmol) in THF (7 mL). The mixture was warmed to room
temperature and zinc dust (200 mg, 3.06 mmol) and HMPT (40
µL) were added. The reaction mixture was refluxed for 3.5 h.
Then H2O (20 mL) and Et2O (20 mL) were added. The aqueous
layer was extracted with Et2O (3 × 30 mL). The combined
organic phases were washed with saturated aqueous CuSO4,
water, and brine and dried over anhydrous Na2SO4. After
removal of the solvent in vacuo, the residue was purified by flash
chromatography (hexane/ethyl acetate; 30:1) to give 8 (122 mg,
1.46, 1.34 (2s, 9H); IR (thin film) 3439, 1749, 1702, 1678 cm-1
.
Ben zyl (2S)-N-ter t-Bu toxyca r bon yl-4-oxo-p r olin a te (4).
CrO3 (17.0 g, 0.17 mol) was added slowly with stirring over 30
min to a solution of pyridine (30 mL) in CH2Cl2 (80 mL) at 0 °C.
The mixture was warmed to room temperature and 3 (6.0 g,
18.69 mmol) in CH2Cl2 (60 mL) was added. The reaction was
stirred vigorously for 4 h at room temperature. The formed dark
solid was decanted and washed with CH2Cl2 (3 × 100 mL). The
organic phases were washed with saturated aqueous NaHCO3,
10% aqueous critic acid, and brine and dried over anhydrous
Na2SO4. The solvent was removed in vacuo to yield an oily
residue, which was purified by flash chromatography (hexane/
ethyl acetate, 3:1) to give 4 (5.0 g, 84%) as a clear oil. [R]20
+
D
1
0.3 (c 1.40, CHCl3); H NMR (300 MHz, CDCl3) δ 7.35 (m, 5H),
5.28-5.09 (m, 2H), 4.88-4.72 (dd, J ) 10.2, 9.3 Hz, 1H), 3.92-
3.87 (d, J ) 13.5 Hz, 2H), 2.97-2.91 (m, 1H), 2.64-2.54 (m, 1H),
1.47, 1.37 (2s, 9H); IR (thin film) 1768, 1748, 1706 cm-1
.
Ben zyl (2S,4S)-N-ter t-Bu toxyca r bon yl-4-h yd r oxy-4-tr i-
flu or om eth yl-L-p r olin a te (5). A solution of 4 (3.0 g, 9.40 mmol)
in THF (45 mL) was cooled to 0 °C, then CF3Si(CH3)3 (1.62 mL,
10.04 mmol) and TBAF (330 µL, 1.0 M in THF) were added. The
mixture was warmed to room temperature and stirred overnight.
The saturated aqueous NH4Cl (15 mL) was added and the
mixture was stirred for 15 min, then TBAF (15 mL, 1.0 M in
THF) was added and the mixture was stirred for 1 h. The organic
layer was separated and the aqueous layer was extracted with
Et2O (3 × 100 mL). The combined organic phases were washed
with water and brine and dried over anhydrous Na2SO4. Filtra-
tion and removal of the solvent in vacuo gave the residue. The
residue was purified by flash chromatography (hexane/ethyl
48%) as a colorless oil. [R]20 -25.1 (c 1.96, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 7.39 (m, 5H), 5.26-5.09 (m, 2H), 4.62-4.45
(dd, J ) 9.3, 9.3 Hz, 1H), 4.14-4.08 (m, 2H), 2.97-2.85 (m, 1H),
2.70-2.62 (m, 1H), 1.47, 1.34 (2s, 9H); 19F NMR (282 MHz,
CDCl3) δ -88 (m, 1F), -91 (m, 1F); IR (thin film) 2978, 1787,
1749, 1705, 1499, 1456, 1393, 1274, 1064, 698 cm-1; MS (EI)
m/z 354 (M+ + 1, 2), 353 (M+, 1) 254 (32), 162 (34), 91 (80), 69
(1), 57 (100). Anal. Calcd for C18H21F2NO4: C, 61.19; H, 5.95;
N, 3.97. Found: C, 61.15; H, 6.07; N, 4.03.
acetate, 10:1) to give 5 (2.97 g, 81%) as a white solid. Mp 68-70
1
°C; [R]20 -12.0 (c 1.54, CHCl3); H NMR (300 MHz, CDCl3) δ
D
7.37-7.36 (m, 5H), 5.30-5.13 (m, 2H), 4.62-4.47 (dd, J ) 9.3,
9.3 Hz, 1H), 3.78-3.68 (m, 2H), 2.63-2.49 (m, 1H), 2.26-2.18
(t, J ) 13.0 Hz, 1H), 1.47, 1.33 (2s, 9H); 19F NMR (282 MHz,
CDCl3) δ -81 (d, J ) 16.6 Hz); IR (KBr) 3377, 2980, 1757, 1707,
1682, 1500, 1479, 1457, 1418, 1178, 1113, 698 cm-1; MS (EI)
m/z 389 (M+, 1), 290 (24), 91 (98), 57 (100). Anal. Calcd for
(2S ,4S )-N -t er t -B u t o x y c a r b o n y l-4-d i flu o r o m e t h y l-
p r olin e (9). Pd/C (520 mg, 10% Pd) was added to a solution of
8 (321 mg, 0.91 mmol) in EtOH (20 mL) and the solution was
hydrogenated at room temperature overnight. After filtration
and removal of the EtOH in vacuo, the residue was purified by
flash chromatography (hexane/ethyl acetate, 1:1) to give 9 (155
mg, 64.3%) as a white solid. Mp 96.5-98.5 °C; [R]20 -77.6 (c
C
18H22F3NO5: C, 55.53; H, 5.66; N, 3.60. Found: C, 55.77; H,
D
0.56, CHCl3); 1H NMR (300 MHz, CDCl3) δ 9.02-8.88 (bs, 1H),
6.02-5.60 (tt, J ) 56, 7.8 Hz; 1H), 4.44-4.28 (dt, J ) 32, 7.5
Hz, 1H), 3.77-3.67 (m, 1H), 3.52-3.42 (m, 1H), 2.78-2.64 (m,
1H), 2.58-2.42 (m, 1H), 2.33-2.09 (m, 1H), 1.49, 1.42 (2s, 9H);
19F NMR (282 MHz, CDCl3) δ -120 (m); 13C NMR(CDCl3, 75.5
MHz) δ 177.9, 176.0, 154.9, 153.5, 119.4, 116.2, 113.0, 81.5, 81.2,
58.3, 46.3, 46.0, 42.2, 41.8, 41.5, 41.2, 40.9, 30.1, 28.8, 28.2, 28.1;
IR (thin film) 3000-2500, 1733, 1637, 1481, 1445, 1370, 1267,
1167, 1151 cm-1; MS (EI) m/z 266 (M+ + 1, 0.5), 265 (M+, 0.4),
220 (M+ - COOH, 3), 164 (M+ - Boc, 47), 120 (M+ - Boc -
COOH, 100), 57 (99). Anal. Calcd for C11H17F2 NO4: C, 49.81;
H, 6.24; N, 5.28. Found: C, 49.97; H, 6.31 N, 5.16.
5.98; N, 3.50.
Ben zyl (2S)-N-ter t-Bu toxyca r bon yl-4-tr iflu or om eth yl-
3,4-d eh yd r op r olin a te (6). A mixture of 5 (123 mg, 0.32 mmol),
dry pyridine (4 mL), and SOCl2 (300 µL) was refluxed under
nitrogen for 20 min. The H2O (1 mL) was added to quench the
reaction. The aqueous layer was extracted with Et2O (3 × 20
mL). The combined organic phases were washed with 1 N HCl
(20 mL), saturated aqueous NaHCO3 (10 mL), water (10 mL),
and brine and dried over anhydrous Na2SO4. After removal of
the solvent in vacuo, the residue was purified by flash chroma-
tography (hexane/ethyl acetate, 30:1) to give 6 (92 mg, 78%) as
a clear oil. [R]20 -175.7 (c 0.92, CHCl3); 1H NMR(300 MHz,
D
CDCl3) δ 7.38-7.35 (m, 5H), 6.29-6.24 (dt, J ) 10.8, 2.1 Hz,
1H), 5.29-5.11 (m, 2H), 5.15-5.11 (m, 1H), 4.43-4.36 (m, 2H),
1.48, 1.34 (2s, 9H);19F NMR (282 MHz, CDCl3) δ -66 (d, J ) 15
Hz); IR (thin film) 2979, 1757, 1708, 1674, 1500, 1458, 1400,
Su p p or tin g In for m a tion Ava ila ble: ORTEP drawing of
the X-ray crystallographic structure of 7. This material is
available free of charge via the Internet at http://pubs.acs.org.
1168, 1128, 697 cm-1; MS (EI) m/z 373 (M+ + 2, 0.3), 372 (M+
+
1, 1), 316 (32), 270 (M+ - Boc, 2), 91 (78), 57 (100). Anal. Calcd
J O0257400
7164 J . Org. Chem., Vol. 67, No. 20, 2002