Asymmetric synthesis of β,β-difluoroamino acids via cross-coupling and Strecker reactions

Article abstract of DOI:10.1016/j.tet.2007.12.002

β,β-Difluoroamino acids were synthesized from commercially available ethyl bromodifluoroacetate using cross-coupling and Strecker reactions as key steps. The coupling reaction of aryl iodides with ethyl bromodifluoroacetate gave the corresponding coupling

Full text of DOI:10.1016/j.tet.2007.12.002

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1731e1735
www.elsevier.com/locate/tet
Asymmetric synthesis of b,b-difluoroamino acids via
cross-coupling and Strecker reactions
*
Xiao-Jin Wang, Fan Zhang, Jin-Tao Liu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
Received 23 August 2007; received in revised form 3 December 2007; accepted 4 December 2007
Available online 21 December 2007
Abstract
b,b-Difluoroamino acids were synthesized from commercially available ethyl bromodifluoroacetate using cross-coupling and Strecker reac-
tions as key steps. The coupling reaction of aryl iodides with ethyl bromodifluoroacetate gave the corresponding coupling products, which were
transformed to 2-difluoromethyl-1,3-oxazolidines in two steps. Boron trifluoride etherate promoted Strecker reaction of 2-difluoromethyl-1,3-
oxazolidines gave a-amino nitriles in good yields and diastereoselectivities. After removal of chiral auxiliary and hydrolysis of the nitrile group,
b,b-difluorophenylalanine was obtained with 73% ee. Partial racemization occurred during the hydrolysis of nitrile group.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Fluorinated amino acid; Bromodifluoroacetate; Cross-coupling reaction; Strecker reaction
1. Introduction
difluorophenylalanine and its derivatives. In this paper we report
a convenient asymmetric synthesis of b,b-difluoroamino acids
starting from ethyl bromodifluoroacetate and aryl iodides.
Fluorinated amino acids have gained an important position
in the synthesis of compounds exhibiting interesting properties
for bioorganic application.1 Among them, gem-difluoroamino
acids and their derivatives have been the subject of consider-
able research because the CF2/CH2 transposition has been rec-
ognized as a valuable tool in the blockage of metabolic
process. b,b-Difluorophenylalanine is an attractive unnatural
amino acid target because of its biological and pharmacolo-
gical properties.2 Two synthetic methods for this fluorinated
amino acid have been developed by direct fluorination. One
utilized the ring-opening reaction of 2-carboxyl-1-phenyl-1-
azirine with hydrogen fluoride pyridine and optically active
isomers were prepared by enzymatic hydrolysis.3 The other
employed a lengthy route containing twice vic-bromofluorina-
tion at the beginning and there was no stereoselectivity during
the construction of the chiral center.4 Therefore it is necessary
to develop more efficient strategies for the synthesis of b,b-
2. Results and discussion
The synthetic route is shown in Scheme 1. The crossing-coup-
ling reaction of aryl halides 1 with ethyl bromodifluoroacetate
F
F
O
TMSCN
BrCF2CO2Et
R
RCF2CO2Et
RI
HN
Ph
3
1
2
Ph
NH2
OH
HN
R
CO2H
*
R
CN
F
F
*
F
F
5
4
* Corresponding author. Tel.: þ86 21 54925188; fax: þ86 21 64166128.
E-mail address: jtliu@mail.sioc.ac.cn (J.-T. Liu).
Scheme 1.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.002

1732
X.-J. Wang et al. / Tetrahedron 64 (2008) 1731e1735
F
F
F
F
a
O
b
c
OMe
+
RCF2CO2Et
R
RI
BrCF2CO2Et
R
HN
OH
Ph
1
2
3
3a (81%, 58:42)
R = a
2a (59%)
2b (65%)
2c (67%)
3b (89%, 62:38)
3c (79%, 78:22)
MeO
b
c
N
SO2Ph
Scheme 2. (a) Cu, DMSO, 55 ꢀC. (b) NaBH4, MeOH, ꢁ55 ꢀC. (c) (S)-phenylglycinol, PPTS, toluene, Dean Stark distillation.
was used to prepare a,a-difluoroesters 2,5 which was next
transformed to oxazolidines 3. Strecker reaction of 3 afforded
the corresponding amino nitriles 4. Removal of the chiral auxi-
liary of 4 followed by hydrolysis gave title compound 5.
Iodobenzene (1a), 4-iodoanisole (1b), and 3-iodo-1–phenyl-
sulfonyl-1H-indole(1c)werechosenas startingmaterials, which
may finally be converted to difluorinated analogs of important
natural phenylalanine, tyrosine, and tryptophan (Scheme 2). In
the presence of copper powder, the cross-coupling reaction of
1 and ethyl bromodifluoroacetate took place readily in DMSO
undermildconditions to givea,a-difluoroesters 2 in good yields.
Reduction of 2 with NaBH4 in methanol gave the corresponding
methyl hemiacetals, which were not stable enough for purifica-
tion by column chromatography and were condensed with
(S)-phenylglycinol directly to give oxazolidines 3, the stable
equivalents of the corresponding imines.6,7
A stereoselective approach to a-amino nitriles was devel-
oped by Brigaud et al. using Lewis acid promoted Strecker re-
action of 2-trifluoromethyl-1,3-oxazolidines.7 Under similar
conditions, diastereomeric mixture of oxazolidines 3 was al-
lowed to react with trimethylsilyl cyanide in the presence of
BF3$OEt2 and a-amino nitriles 4 were obtained in high yields
with good diastereoselectivities (Scheme 3). The absolute con-
figuration of the major product was determined by X-ray crys-
tallographic studies (Fig. 1).8 The formation of an iminium ion
intermediate has been proposed for the good diastereoselectiv-
ity of the above Strecker reaction.7 The existence of the inter-
mediate in our reaction was partially proved by a simple NMR
experiment. When BF3$OEt2 was added to a CDCl3 solution
Figure 1. ORTEP of the crystal structure of 4a (major isomer).
NMR spectrum. Therefore the nucleophilic attack took place
mainly from the Si face to give major diastereomer with
(S,S) configuration due to the hindering effect of phenyl in
the iminium ion intermediate (Fig. 2).9
Compound 4a was chosen as an example for the following
transformations. The chiral auxiliary of 4a was removed by re-
acting with lead tetraacetate in a mixed solvent of dichlorome-
thane and methanol. After hydrolysis of the nitrile group with
1
of 3a, new signals appeared for protons of imine in its H
Ph
Ph
F
F
OH
OH
+
HN
F
HN
F
O
BF3·OEt2
R
+
TMSCN
R
R
CH2Cl2, -78 °C
CN
CN
HN
F
F
Ph
4a (93%, 93:7)
3a-c
4b (92%, 90:10)
4c (85%, 98:2)
Scheme 3. Strecker reaction of 3 and TMSCN.

X.-J. Wang et al. / Tetrahedron 64 (2008) 1731e1735
1733
F
F
(50 mLꢂ3). The ethereal solution was washed with saturated
NaCl solution and dried over Na2SO4. After removal of sol-
vent, the crude product was added to a solution of (S)-phenyl-
glycinol (685 mg, 5 mmol) and PPTS (20 mg) in toluene, and
the resulted mixture was refluxed to remove water by azeo-
tropic distillation until no water was separated. After
R
NH
H
O
BF3OEt2
H
Figure 2.
Ph
Ph
OH
NH2
HN
F
N
b
a
CO2H
CN
CN
F
F
F
F F
5a (60%, 73% ee)
Scheme 4. (a) Pb(OAc)4, CH2Cl2/MeOH (2:1), 0 ꢀC. (b) (1) concd HCl, 100 ꢀC, 3 h; (2) Dowex Hþ, 2% NH4OH.
4a (major isomer)
concentrated HCl and ion-exchange resin purification, b,b-di-
removal of toluene under reduced pressure, the residue was
purified by flash chromatography to give 3.
fluorophenylalanine 5a was obtained in 50% overall yield
from 4a (Scheme 4). The enantiomeric excess of 5a was deter-
mined by NMR analysis of its methyl ester in the presence of
Eu(tfc)3.3a Unfortunately, only 73% ee was achieved. Partial
racemization occurred during the hydrolysis of nitrile group,
since complete racemization was observed when 4a was
treated with concentrated HCl solution for a long time.4 At-
tempt to improve ee value by changing reaction temperature
and hydrolytic media failed to give better result.
4.2.1. (4S)-2-(Difluoro(phenyl)methyl)-4-phenyloxazolidine
(3a)
Colorless oil. IR (film): n 3363, 2887, 1452, 1103,
1058 cmꢁ1; 1H NMR (300 MHz, CDCl3): d 2.56 (s, 1H), 3.38
(t, J¼8.7 Hz, 0.42H), 3.64 (t, J¼7.8 Hz, 0.58H), 4.00 (q,
J¼4.2 Hz, 0.58H), 3.99e4.18 (m, 1H), 4.44 (q, J¼7.8 Hz,
0.42H), 5.21e5.24 (m, 1H), 7.22e7.35 (m, 5H), 7.43e7.47
(m, 3H), 7.60e7.64 (m, 2H); 19F NMR (282 MHz, CDCl3):
d ꢁ107.8, ꢁ111.4 (AB, JAB¼250.7 Hz, 1.16F), ꢁ108.3,
ꢁ111.4 (AB, JAB¼252.4 Hz, 0.84F); MS (m/z, %): 275 (Mþ,
1), 148 (100); Anal. Calcd for C16H15F2NO: C, 69.81; H,
5.49; N, 5.09. Found: C, 69.59; H, 5.57; N, 4.90.
3. Conclusion
In summary, we have developed a short and efficient
method for the synthesis of b,b-difluoroamino acids. The strat-
egy employed easily available ethyl bromodifluoroacetate as
the difluoromethylene precursor and the cross-coupling reac-
tion of aryl iodides with ethyl bromodifluoroacetate and
BF3$OEt2 promoted Strecker reaction as key steps.
4.2.2. (4S)-2-(Difluoro(4-methoxyphenyl)methyl)-4-
phenyloxazolidine (3b)
Colorless oil. IR (film): n 3363, 2889, 1616, 1518, 1254,
;
1071 cmꢁ1 1H NMR (CDCl3, 300 MHz): d 2.55 (br, 1H),
4. Experimental
3.40 (t, J¼7.8 Hz, 0.38H), 3.64 (t, J¼7.5 Hz, 0.62H), 3.84
(s, 3H), 4.01 (q, J¼5.1 Hz, 0.62H), 4.13e4.19 (m, 1H), 4.44
(q, J¼7.5 Hz, 0.38H), 5.10e5.21 (m, 1H), 6.95 (d,
J¼9.0 Hz, 2H), 7.24e7.34 (m, 5H), 7.52e7.56 (m, 2H); 19F
4.1. General
Melting points were uncorrected. H NMR and 13C NMR
spectra were recorded on a Bruker AM-300 spectrometer.
19F NMR spectra were taken on
(282 MHz) spectrometer using CFCl3 as external standard.
IR spectra were obtained with a Nicolet AV-360 spectropho-
tometer. Mass spectra and high-resolution mass spectra
(HRMS) were obtained on a Finnigan GCeMS 4021 and a Fin-
nigan MAT-8430 spectrometer, respectively. The known com-
pounds 2aec5 were prepared according to literature. The
diastereomeric ratio of 3 and 4 was determined by 19F NMR.
NMR (CDCl3, 282 MHz):
d
ꢁ106.3, ꢁ110.0 (AB,
1
JAB¼251.0 Hz, 1.24F), ꢁ116.8, ꢁ110.1 (AB, JAB¼252.7 Hz,
0.76F); MS (m/z, %): 306 (Mþþ1, 5.15), 157 (17.56), 149
(11.49), 148 (100.00), 121 (9.44), 120 (80.76), 103 (25.33);
Anal. Calcd for C17H17F2NO2: C, 66.87; H, 5.61; N, 4.59.
Found: C, 66.47; H, 5.80; N, 4.30.
a Bruker AM-300
4.2.3. (4S)-2-(Difluoro(1-(phenylsulfonyl)-1H-indol-3-yl)-
methyl)-4-phenyloxazolidine (3c)
Yellow oil. IR (film): n 3359, 2887, 1712, 1448, 1377,
1178, 1134, 1090 cmꢁ1
;
1H NMR (CDCl3, 300 MHz):
4.2. General procedure for the preparation of 3
d 2.61 (br, 1H), 3.29 (t, J¼8.4 Hz, 0.22H), 3.60 (t,
J¼7.5 Hz, 0.78H), 3.95e4.00 (m, 0.78H), 4.06e4.14 (m,
1H), 4.41e4.47 (m, 0.22H), 5.22e5.32 (m, 1H), 7.13e7.51
(m, 10H), 7.79e8.01 (m, 5H); 19F NMR (CDCl3, 282 MHz):
d ꢁ103.4, ꢁ105.4 (AB, JAB¼265.4 Hz, 1.56F), ꢁ103.6,
ꢁ105.8 (AB, JAB¼267.7 Hz, 0.44F); MS (ESI, m/z, %):
NaBH4 (190 mg, 5 mmol) was added in portion to a solution
of 2 (5 mmol) in MeOH (5 mL) at ꢁ60 ꢀC. After addition, the
reaction mixture was stirred for 1 h at ꢁ50 ꢀC. Then 10 mL of
10% HCl was added and the mixture was extracted with ether

1734
X.-J. Wang et al. / Tetrahedron 64 (2008) 1731e1735
455.2 (Mþþ1); Anal. Calcd for C24H20F2N2O3S: C, 63.42; H,
J¼31.2 Hz); MS (ESI, m/z, %): 504.2 (MþNaþ); HRMS
Calcd for C25H21F2N3O3S (MþNa): 504.1154; Found:
504.11639.
4.44; N, 6.16. Found: C, 63.16; H, 4.50; N, 5.97.
4.3. General procedure for Strecker reaction
4.4. The preparation of 5a
To a solution of oxazolidines 3 (0.5 mmol) in dichlorome-
thane (5 mL) under nitrogen atmosphere were added cyanotri-
methylsilane (99 mg, 1 mmol) and BF3$OEt2 (142 mg,
1 mmol) at ꢁ78 ꢀC. The reaction mixture was stirred for
8 h. After warming to room temperature, the mixture was
poured into a saturated aqueous solution of NaHCO3
(25 mL). The aqueous layer was extracted with dichlorome-
thane (3ꢂ25 mL), and the combined organic extracts were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. Purification of the residue by flash chromatography
gave pure major isomer of 4.
To a solution of 4a (151 mg, 0.5 mmol) in 5 mL of MeOH
and 10 mL of CH2Cl2 was added Pb(OAc)4 (332 mg,
0.75 mmol) at 0 ꢀC. After 30 min of stirring at 0 ꢀC, the reac-
tion mixture was poured into an aqueous phosphoric acid
buffer solution (15 mL) at room temperature and then filtered
on Celite. The aqueous layer was extracted with dichlorome-
thane (3ꢂ15 mL). The combined organic extracts were dried
over Na2SO4, filtered, and concentrated under reduced pres-
sure. The crude product was mixed with 5 mL of concentrated
HCl, and the mixture was stirred for 3 h at 100 ꢀC. After cool-
ing to room temperature, the reaction mixture was extracted
with ether (30 mL), and the aqueous solution was concentrated
under reduced pressure to give the crude product. Pure 5a was
obtained after purification with ion-exchange resin.
4.3.1. (S)-3,3-Difluoro-2-[(S)-2-hydroxy-1-phenylethyl-
amino]-3-phenylpropanenitrile (4a)
Colorless solid. Mp: 136e137 ꢀC; [a]D25 ꢁ136.3 (c 0.48,
CHCl3); IR (KBr): n 3473, 1453, 1064, 1024 cmꢁ1 1H
;
NMR (300 MHz, CDCl3):
d 1.70 (s, 1H), 2.60 (d,
4.4.1. (S)-2-Amino-3,3-difluoro-3-phenylpropanoic acid
(5a)
J¼13.5 Hz, 1H), 3.48e3.54 (m, 1H), 3.74e3.88 (m, 2H),
4.04e4.09 (m, 1H), 7.03 (d, J¼6.3 Hz, 2H), 7.23e7.28 (m,
3H), 7.44e7.56 (m, 5H); 19F NMR (282 MHz, CDCl3):
d ꢁ98.3, ꢁ107.0 (AB, JAB¼250.1 Hz, 2F); MS (m/z, %):
303 (MþþH, 5), 271 (100); Anal. Calcd for C17H16F2N2O:
C, 67.54; H, 5.33; N, 9.27. Found: C, 67.66; H, 5.18; N, 9.19.
White solid. Mp: 170e171 ꢀC. [a]2D5 ꢁ47.6 (c 0.22, 1.2 N
HCl); IR (KBr):
n 3012, 1639, 1601, 1513, 1066,
1034 cmꢁ1
; d 4.26 (dd,
1H NMR (300 MHz, D2O):
J1¼20.4 Hz, J2¼6.3 Hz, 1H), 7.38e7.44 (m, 5H); 19F NMR
(282 MHz, D2O): d ꢁ93.5, ꢁ108.6 (AB, JAB¼247.0 Hz,
2F); 13C NMR (75 MHz, D2O): d 66.8 (t, J¼27.2 Hz), 122.3
(t, J¼247.1 Hz), 128.3 (t, J¼6.4 Hz), 128.8, 131.3, 132.3 (t,
J¼24.5 Hz), 167.2; MS (ESI, m/z, %): 202.2 (Mþ); HRMS
Calcd for C9H10F2NO2: 202.0674; Found: 202.0673.
4.3.2. (S)-3,3-Difluoro-2-[(S)-2-hydroxy-1-phenylethyl-
amino]-3-(4-methoxyphenyl)propanenitrile (4b)
Yellow oil. [a]2D5 ꢁ90.8 (c 1.10, CHCl3); IR (film): n 3493,
3339, 1613, 1518, 1328, 1256, 1179 cmꢁ1; H NMR (CDCl3,
1
300 MHz): d 2.04 (s, 1H), 2.57 (d, J¼12.9 Hz, 1H), 3.45e3.55
(m, 1H), 3.72e3.81 (m, 2H), 3.86 (s, 3H), 4.03e4.08 (m, 1H),
6.95 (d, J¼9.0 Hz, 2H), 7.07e7.10 (m, 2H), 7.23e7.28 (m,
3H), 7.41 (d, J¼7.8 Hz, 2H); 19F NMR (CDCl3, 282 MHz):
d ꢁ97.2, ꢁ104.5 (AB, JAB¼249.0 Hz, 2F); 13C NMR
(CDCl3, 75 MHz): d 161.5, 137.0, 128.9, 128.5, 127.7,
127.6, 127.5, 124.7 (t, J¼25.6 Hz), 118.7 (t, J¼249.2 Hz),
115.8, 113.8, 67.2, 62.7, 55.5, 55.2 (t, J¼33.6 Hz); MS (ESI,
m/z, %): 333 (Mþþ1); HRMS Calcd for C18H19F2N2O2
(Mþ1): 333.1410; Found: 333.14091.
4.4.2. Determination of ee value of compound 5a
SOCl2 (1 mL) was added dropwise to a solution of 5a
(10 mg, 0.05 mmol) in methanol (5 mL) under stirring at
ꢁ10 ꢀC. The mixture was allowed to warm up to room temper-
ature and then refluxed for 24 h. After removal of methanol
and excess SOCl2, the residue was dissolved in saturated aque-
ous NaHCO3 solution (5 mL) and stirred for 0.5 h. The reac-
tion mixture was extracted with ether (20 mLꢂ3). The
ethereal layer was combined and washed with saturated aque-
ous NaCl solution (30 mL), dried over Na2SO4, and concen-
trated in vacuum. The crude product was directly dissolved
in CDCl3 and Eu(tfc)3 (18 mg, 0.02 mmol) was added to the
solution. The ee value of 5a could be easily determined by
its 19F NMR spectrum.
4.3.3. (S)-3,3-Difluoro-2-[(S)-2-hydroxy-1-phenylethyl-
amino]-3-[1-(phenylsulfonyl)-1H-indol-3-yl]-
propanenitrile (4c)
Yellow oil. [a]2D5 ꢁ72.2 (c 1.00, CHCl3); IR (film): n 3336,
2930, 1449, 1380, 1190, 1136 cmꢁ1 1H NMR (CDCl3,
;
Acknowledgements
300 MHz): d 2.05 (s, 1H), 2.78 (d, J¼12.6 Hz, 1H), 3.42e
3.49 (m, 1H), 3.70e3.75 (m, 1H), 3.88e4.00 (m, 1H),
4.02e4.08 (m, 1H), 6.88e7.59 (m, 11H), 7.89e8.03 (m,
4H); 19F NMR (CDCl3, 282 MHz): d ꢁ93.6, ꢁ103.0 (AB,
JAB¼260.8 Hz, 2F); 13C NMR (CDCl3, 75 MHz): d 137.6,
136.6, 134.7, 134.5, 129.6, 128.8, 128.5, 127.5, 127.0, 126.8
(t, J¼8.2 Hz), 126.4, 125.7, 124.2, 120.4, 117.7 (t,
J¼219.0 Hz), 115.4, 115.0, 114.4, 113.7, 66.9, 62.7, 54.3 (t,
We thank the National Natural Science Foundation of
China for financial support (no. 20572124).
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