Asymmetric synthesis of both enantiomers of anti-4,4,4-trifluorothreonine and 2-amino-4,4,4-trifluorobutanoic acid

Article abstract of DOI:10.1021/jo0344384

A short and efficient enantio selective synthesis of both enantiomers of anti-4,4,4-trifluorothreonine and 2-amino-4,4,4-trifluorobutanoic acid was successfully developed. Trifluoromethylation of benzyl-protected bromoalkene 4 provided key intermediate trifluoromethylated transdi-substituted alkene 2 in good yield. The sequence then involved Sharpless asymmetric dihydroxylation, nucleophilic opening of cyclic sulfate with NaN₃, palladium-catalyzed selective hydrogenation, and oxidation.

Full text of DOI:10.1021/jo0344384

Supporting Information
anti
Asymmetric Synthesis of both Enantiomers of
2-Amino-4,4,4-trifluorobutanoic Acid
-4,4,4-Trifluorothreonine and
Zhong-Xing Jiang,§ Ying-Ying Qin, ¶ and Feng-Ling Qing,*, §, ¶
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, 354 Fenglin Lu, Shanghai 200032, China
and College of Chemistry and Chemistry Engineering, Donghua University, 1882
West Yanan Lu, Shanghai 200051, China
S1 S2
3, 4,1 2, 5
4, 1
S3
S4
S5
S6
Characterization
data of compound
6′, 7′, 8′
9′, 10′, 11′, 12′ 13′, 14′, 15′
Procedure
compound
for
3
2
(E)-3-Bromo-2-propene-1-ol (3) Br2 (48.00 g, 300 mmol) was added to a vigorously
o
stirring solution of KOH (45.00 g) in water (120 mL) at –5 C. The yellow solution
was kept at 0 oC and added dropwise for 3 h to a solution of propargyl alcohol (17.83
g, 1.06 equiv; freshly distilled) in water (39 mL) at –7 oC - 0 oC. The reaction mixture
o
was warmed to 10 C and then extracted 4 times with ether. The organic layer was
washed with Na2S2O3, dried over K2CO3. The solvent was removed to provide the
crude 1-bromopropyne-3-ol (CAUTION: the 1-halopropynes are potentially
explosive. Do not heat these compounds). A 2 L flask charged with LiAlH4 (20.30 g,
2.0 equiv) was carefully added anhydrous ether (150 mL) at –5 oC with stirring. Then
a solution of AlCl3 (53.50 g, 1.0 equiv) in anhydrous ether (150 mL) was carefully
added. The crude 1-bromopropyne-3-ol, prepared in the first step, was added dropwise
and the mixture was refluxed for 4 h. The reaction was quenched with wet ether
(water saturated, 200 mL), followed by water (20 mL) and 5 % NaOH (20 mL) at –10
S1

oC. Then water (60 mL) was added to break up the solid mass. The liquid was
decanted and extracted with ether (3 200 mL). The combined organic layer was dried
over K2CO3 and concentrated. The residue was distilled at reduced pressure (67 oC / 84
1
mmHg) to yield 3 (31.26 g, 79 % from propargyl alcohol). H NMR (300 MHz,
CDCl ) 6.34-6.36 (m, 2H), 4.11-4.13 (m, 2H).
δ
3
(E)-1-Benzyloxy-3-bromo-2-butene (4) NaH (10.03 g, 50 %, 209 mmol) was
o
added at 0 C to a solution of (E)-3-bromo-2-propene-1-ol 3 (24.00 g, 174 mmol) in
THF (200 mL). After the mixture was stirred for 30 min, benzyl bromide (35.27 g,
209 mmol) and tetrabutylammonium iodide (0.71 g) was added. The reaction mixture
was stirred for 4 h at room temperature. Water (200 mL) was added. The mixture was
extracted with dichloromethane. The combined organic layer was dried over Na2SO4
and concentrated in vacuo. The residue was purified by flash chromatography on
1
silica gel (petroleum ether : ethyl acetate = 20:1) to give 4 (37.69 g, 95 %). H NMR
(300 MHz, CDCl3) δ 7.29-7.38 (m, 5H), 6.32-6.41 (m, 2H), 4.52 (s, 2H), 3.97-3.99
(m, 2H).
To a solution of LDA (440 mmol) in THF (400
4,4,4-Trifluoro-2-butyn-1-ol (1)
mL) was added dropwise a solution of 2-bromo-3,3,3-trifluoropropane (35.00 g, 200
o
mmol) in THF (200 mL) at –78 C. After the mixture was stirred for 10 min,
paraformaldehyde (12.00 g, 400 mmol) was added and the whole was stirred for 3 h at
o
–78 C. Then the stirring mixture was allowed to warm to room temperature
overnight. The reaction mixture was quenched 1N HCl solution (1000 mL) and
extracted three times with ether. The organic layer was dried over Na2SO4 and
concentrated. The residue was distilled (70 oC / 80mmHg) to give 1 (7.44 g, 30 %). 19F
NMR (282 MHz, CDCl ) –51.34 (t, J = 3.1 Hz).
δ
3
S2

E
To a solution of
( )-1-Benzyloxy-4,4,4-trifluoro-2-butene (2) ( prepared from 1):
Red-Al (25.0 mmol) in toluene (30 mL) at –78 oC was added
4,4,4-trifluoro-2-butyn-1-ol 1 (21.2 mmol). After the reaction was stirred for 3 h at
that temperature, it was quenched with 1 N HCl (100 mL) and extracted three times
with ether. The organic layer was dried over Na2SO4 and concentrated. The residue
was then dissolved in THF (50 mL). To the solution was added a slurry of NaH (1.10
g, 50 %, 22.3 mmol) at 0 oC. The reaction mixture was stirred for 30 min, then benzyl
bromide (3.85 g, 22.3 mmol) and tetrabutylammonium iodide (0.50 g) was added. The
reaction mixture was stirred for 4 h at room temperature. Water (50 mL) was added
dropwise to the mixture. The reaction mixture was extracted with dichloromethane,
dried over Na2SO4 and the solvent was removed. The residue was purified by flash
chromatography on silica gel (petroleum ether: ethyl acetate = 20:1) to give (3.43 g,
2
75 %). 1H NMR (300 MHz, CDCl3) δ 7.29-7.39 (m, 5H), 6.36-6.48 (m, 1H), 5.93-6.00
19
(m, 1H), 4.57 (s, 2H), 4.10-4.15 (m, 2H); F NMR (282 MHz, CDCl3) δ –64.22 (m);
IR (thin film) max 3091, 3035, 2860, 1687, 1498, 1455, 1315, 1119 cm-1; MS (EI) m/z
ν
216 (M+, <1), 91 (100), 77 (15), 69 (3). HRMS EI Calcd for C11H11OF3: 216.0762.
Found: 216.0745.
R,
(2
S
This compound was
3 )-1-Benzyloxy-4,4,4-trifluoro-2,3-butanediol (5′).
prepared in 94 % yield and 93 % ee by using the same procedure as described for 5:
mp 71-72 oC, [α]20D = + 13.8 (c 0.98, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.30-7.39
(m, 5H), 4.57 (s, 2H), 4.14 (dt, J = 1.8 Hz, 5.7 Hz, 1H), 3.95 (dq, J = 1.8 Hz, 7.5 Hz,
1H), 3.60 (d, J = 5.7 Hz, 2H); 19F NMR (282 MHz, CDCl ) –77.45 (d, J = 7.5 Hz);
δ
3
IR ( KBr ) max 3338, 3035, 1588, 1499, 1455, 1164, 1143 cm-1; MS (EI) m/z 250 ( M+,
ν
25 ), 107 ( 15 ), 91 ( 100 ), 77 ( 5 ), 69 ( 1 ). Anal. Calcd for C11H13O3F3: C, 52.80; H,
5.24. Found: C, 52.63; H, 5.11.
(3S,
4R)-3-Benzyloxymethyl-4-trifluotomethyl-2,2-dioxo-1,3,2-dioxathiolane
This compound was prepared in 92 % yield by using the same procedure as
(6′).
S3

1
described for : [ ]20 = - 22.7 (c 1.11, CHCl3); H NMR (300 MHz, CDCl3)
6
α
δ
D
7.35-7.43 (m, 5H), 5.22 (dq, J = 5.9 Hz, 6.0 Hz, 1H), 5.07 (dt, J = 6.3 Hz, 3.6 Hz,
1H), 4.71 (d, J = 11.7 Hz, 1H), 4.64 (d, J = 11.7 Hz, 1H), 3.95 (dd, J = 3.6 Hz, 12.0
Hz, 1H), 3.81 (dd, J = 3.6 Hz, 12.0 Hz, 1H); 19F NMR (282 MHz, CDCl3) δ –77.26 (d,
J = 5.9 Hz); IR ( thin film ) max 3035, 1498, 1456, 1409, 1220, 1160 cm-1, MS (EI) m/z
ν
312 (M+, 34 ), 107 ( 32 ), 91 (100 ), 77 (8), 69 (2). Anal. Calcd for C11H11O5F3S: C,
42.31; H, 3.55. Found: C, 42.35; H, 3.66.
(2S, 3S)-1-Benzyloxy-2-azido-4,4,4-trifluorobutan-3-ol (7′). This compound was
prepared in 94 % yield by using the same procedure as described for 7: [ ]20D = -17.3
α
1
(c 1.00, CHCl3); H NMR (300 MHz, CDCl3) 7.29-7.39 (m, 5H), 4.58 (s, 2H),
δ
4.10-4.20 (m, 1H), 3.93 (dd, J = 4.9 Hz, 9.4 Hz, 1H), 3.90 (dd, J = 3.1 Hz, 9.4 Hz,
19
1H), 3.61-3.65 (m, 1H); F NMR (282 MHz, CDCl3) δ –76.53 (d, J = 6.6 Hz); IR (
thin film) νmax 3437, 3035, 2115, 1456, 1270, 1141 cm-1, MS (EI) m/z 247 (1), 107 (1),
91 (100), 77 (5), 69 (1). Anal. Calcd for C11H12O2F3N3: C, 48.00; H, 4.40; N, 15.27.
Found: C, 47.95; H, 4.68; N,14.71.
(2S, 3S)- 2-(tert-Butoxycarbonyl)amino-4,4,4-trifluoro-1,3-butandiol (8′). This
compound was prepared in 88 % yield by using the same procedure as described for
o
1
8: mp 94-95 C; [ ]20 = + 3.7 (c 1.12, CHCl3); H NMR (300 MHz, CD3OD)
α
δ
D
3.98-4.06 (m, 1H), 3.81-3.87 (m, 1H), 3.68-3.76 (m, 2H), 1.42 (s, 9H); 19F NMR (282
MHz, CD OD) –77.49 (d, = 6.5 Hz); IR ( KBr ) max 3371, 2991, 1689, 1532, 1164
δ
J
ν
3
cm-1, MS (EI) m/z 228 ( 3 ), 160 ( 15 ), 99 ( 1 ), 69 ( 2 ), 57 ( 100 ). Anal. Calcd for
C9H16O4NF3: C, 41.70; H, 6.22; N, 5.40. Found: C, 41.70; H, 6.28; N, 5.16.
R, S
tert
This compound was prepared in 80 % yield by using the same procedure as
(2 3 )-2-( -Butoxycarbonyl)amino-3-hydroxy-4,4,4-trifluorobutanioc acid
(10′).
described for 10: mp 106-107 oC; [α]20D = +34.1 (c 1.08, CHCl3); 1H NMR (300 MHz,
19
CD3OD) δ 4.40 (d, J = 7.2 Hz, 1H), 4.21-4.30 (m, 1H), 1.40 (s, 9H); F NMR (282
MHz, CD OD) –77.50 (d, J = 7.1 Hz); IR ( KBr ) max 3398, 2989, 1741, 1673, 1524,
δ
ν
3
S4

1144 cm-1, MS (EI)
228 ( <1 ), 174 ( 8 ), 172 ( 2 ), 99 (1), 69 ( 1 ), 57 ( 100 ).
m/z
Anal. Calcd for C9H14O5NF3: C, 39.57; H, 5.16; N, 5.13. Found: C, 39.53; H, 5.24; N,
5.04.
(2R, 3S)-2-Amino-3-hydroxy-4,4,4-trifluorobutanioc acid (11 ). This compound
′
was prepared in 100 % yield by using the same procedure as described for : [ ]20
=
11 α
D
1
+ 11.8 (c 0.58, H O); H NMR (300 MHz, D O) 4.38 (dq, = 4.2 Hz, 6.3 Hz, 1H),
δ
J
2
2
3.75 (d, J = 4.2 Hz, 1H); 19F NMR (282 MHz, D2O) δ –75.09 (d, J = 6.4 Hz).
(2S, 3S)-1-Benzyloxyl-2-(tert-butoxycarbonyl)amino-4,4,4-trifluorobutan-3-ol
This compound was prepared in 91 % yield by using the same procedure as
(9′).
o
1
describled for : mp 59-60 C; [ ]20 = -8.5 (c 1.22, CHCl3); H NMR (300 MHz,
9
α
D
CDCl3) δ 7.30-7.42 (m, 5H), 5.40 (d, J = 8.7 Hz, 1H), 4.55 (d, J = 12.8 Hz, 1H), 4.53
(d, J = 12.8 Hz, 1H), 4.06-4.16 (m, 2H), 3.95 (dd, J = 3.0 Hz, 10.2 Hz, 1H), 3.71 (dd,
19
J = 1.8 Hz, 10.2 Hz, 1H), 1.46 (s, 9H); F NMR (282 MHz, CDCl ) –76.74 (d, J =
δ
3
9.6 Hz); IR ( KBr )
3420, 2981, 1695, 1512, 1164 cm-1, MS (EI) m/z 350 ( M+1,
νmax
1), 91 (76), 77 (3), 69 (1), 57 (100). Anal. Calcd for C16H22O4NF3: C, 55.01; H, 6.36;
N, 4.01. Found: C, 55.07; H, 6.63; N, 3.86.
(2S,3S)-1-Benzyloxyl-2-(tert-butoxycarbonyl)amino-3-oxylthiocarbonylphenyl-
This compound was prepared in 80 % yield by using the
4,4,4-trifluorobutane (12′).
1
same procedure as described for : [ ]20 = -43.6 (c 0.59, CHCl3); H NMR (300
12
α
D
MHz, CDCl3) δ 7.44 (dt, J = 1.8 Hz, 7.8 Hz, 2H), 7.31-7.36 (m, 5H), 7.09 (d, J = 7.8
Hz, 2H), 7.13-7.18 (m, 1H), 5.12 (d, J = 9.0 Hz, 1H), 4.56 (s, 2H), 4.48-4.54 (m, 2H),
3.66-3.72 (m, 2H), 1.47 (s, 9H); 19F NMR (282 MHz, CDCl ) –72.76 (d, J = 8.5 Hz);
δ
3
IR ( thin film )
3450, 2980, 1719, 1592, 1492, 1269, 1170 cm-1, MS (EI) m/z 486
νmax
(M+, 1), 107 ( 21 ), 91 (100), 77 (11), 69 ( 1 ), 57 ( 92 ). HRMS (ESI) Calcd for
C23H26O5NF3S Na: 508.1376. Found: 508.1376.
S5

R
tert
This
(2 )-1-Benzyloxyl-2-( -butoxycarbonyl)amino-4,4,4-trifluorobutane (13′).
compound was prepared in 85 % yield by using the same procedure as described for
o
1
13: mp 56-57 C; [α]20 = -25.2 (c 0.73, CHCl3); H NMR (300 MHz, CDCl3) δ
D
7.30-7.41 (m, 5H), 4.97 (d, J = 6.9 Hz, 1H), 4.56 (d, J = 12.0 Hz, 1H), 4.52 (d, J =
12.0 Hz, 1H), 4.11-4.14 (m, 1H), 3.49-3.60 (m, 2H), 2.39-2.52 (m, 2H), 1.44 (s, 9H);
19F NMR (282 MHz, CDCl ) –64.03 (t, = 10.7 Hz); IR ( KBr )
3365, 2988,
δ
J
νmax
3
1684, 1533, 1244, 1170 cm-1, MS (EI) m/z 307 ( <1 ), 276 ( 1 ), 107 ( 12 ), 91 (92), 77
(3), 69 ( 1 ), 57 ( 100 ). Anal. Calcd for C16H22O3NF3: C, 57.65; H, 6.65; N, 4.20.
Found: C, 57.13; H, 6.61; N, 3.86.
R
tert
This
(2 )-2-( -Butoxycarbonyl)amino-4,4,4-trifluorobutan-1-ol
(14′).
compound was prepared in 99 % yield by using the same procedure as described for
o
1
14: mp 94-95 C; [α]20 = -19.5 (c 0.48, CHCl3); H NMR (300 MHz, CDCl3) δ
D
3.93-3.95 (m, 1H), 3.69-3.71 (m, 2H), 2.34-2.47 (m, 2H), 1.43 (s, 9H); 19F NMR (282
MHz, CDCl ) –63.58 (t, J = 9.6 Hz); IR ( KBr ) max 3363, 2984, 1685, 1533, 1242,
δ
ν
3
1144 cm-1, MS (EI) m/z 244 ( M+1, <1), 112 (22), 69 (1), 57 (100). Anal. Calcd for
C9H16O3NF3: C, 44.44; H, 6.63; N, 5.76. Found: C, 44.59; H, 6.59; N, 5.47.
(2R)-2-(tert-Butoxycarbonyl)amino-4,4,4-trifluorobutanioc acid (15 ) This
′
compound was prepared in 79 % yield by using the same procedure as described for
1 : [ ]20 = +7.6 (c 0.85, CHCl ); 1H NMR (300 MHz, Acetone-d ) 6.51 (d, = 8.4
5 α
δ
J
D
3
6
19
Hz, 1H), 4.49 (dt, J = 4.2 Hz, 8.4 Hz, 1H), 2.72-2.91 (m, 2H), 1.41 (s, 9H); F NMR
(282 MHz, Acetone-d6) δ –64.99 (t, J = 12.4 Hz).
S6