General and practical conversion of aldehydes to homologated carboxylic acids

Article abstract of DOI:10.1021/ol8016484

(Chemical Equation Presented) The reaction of aldehydes with trichloromethide followed by sodium borohydride or sodium phenylseleno(triethyl) borate under basic conditions affords homologated carboxylic acids in high yields. This operationally simple procedure provides a practical, efficient alternative to other homologation protocols. The approach is compatible with sensitive aldehydes including enals and enolizable aldehydes. It also offers convenient access to α-monodeuterated carboxylic acids.

Full text of DOI:10.1021/ol8016484

Supporting Information
General and Practical Conversion of Aldehydes to
Homologated Carboxylic Acids
Lauren R. Cafiero and Timothy S. Snowden*
Department of Chemistry, The University of Alabama, Tuscaloosa, Alabama, 35487, USA
snowden@bama.ua.edu
General Experimental Section
S1
Preparation of Aliphatic, Alkenyl, and Aromatic Trichloromethyl Carbinols S1
Preparation of One-Carbon Homologated Carboxylic Acids
References
H/ C Spectra of Reported Major Products
S5
S11
S12
1
13

General Information.
1
13
The H and C NMR spectra were recorded at 500 MHz and 125 MHz respectively.
All melting points are uncorrected. High-resolution mass spectra for the trichloromethyl
TM
carbinols were recorded on an AutoSpec-Ultima NT mass spectrometer using electron
ionization (EI) at 70 eV. High resolution mass spectra for the carboxylic acids were
recorded on a Micromass Q-TOF Ultima instrument with an electrospray probe and a Z-
spray source. Optical rotation was determined on a Perkin-Elmer 241 digital polarimeter;
concentration c is reported as g/100 mL. All reagents were used directly as obtained from
commercial sources unless otherwise noted. All melting points are uncorrected. TLC
visualization was achieved by UV light (254nm) and KMnO staining.
4
Synthesis of Aliphatic, Alkenyl, and Aromatic Trichloromethyl Carbinols.
Trichloromethyl carbinols in entries 2a-e and 2l-n were prepared by the method of Corey
1
and Link from the respective aldehydes. Yields and reaction times are unoptimized.
The following serves as a general procedure: To a solution of aldehyde (1 mmol) in
1
.35mL of anhydrous DMF was added trichloroacetic acid (1.5 mmol) then sodium
trichloroacetate (1.5 mmol) with stirring at room temperature. Initially rapid evolution of
CO was observed. After 6-8 h, the mixture was monitored by TLC. If starting material
2
remained, one equivalent of sodium trichloroacetate and trichloroacetic acid was added.
After an additional 4-8 h, the mixture was diluted with 5 mL of diethyl ether and washed
with saturated aqueous sodium bicarbonate. Precipitated solids were filtered and washed
three times with diethyl ether. The filtrate was washed two more times with sodium
bicarbonate solution and once with brine. The organic phase was dried with sodium
sulfate, and the solvent was evaporated under reduced pressure. The resulting residue
was eluted through a plug of silica gel with indicated ratios of hexane/ethyl acetate to
afford the corresponding trichloromethyl carbinol.
2
Trichloromethyl carbinols in entries 2f-k were prepared by the method of Wyvratt from
the respective aldehydes, without modification.
1
,1,1-Trichlorononan-2-ol (2a)
The crude material was purified by flash chromatography through a plug of silica gel,
using 95:5 hexane/EtOAc as the eluant. The indicated compound was obtained as a
-1
yellow oil in 93% yield. IR (film): 3578 (b), 2959 (s), 2929 (s), 1265 (s), 748 (s) cm ;
1
H NMR (CDCl , 500 MHz) δ ppm: 3.99 (d, 1H, J = 8.9 Hz), 2.77 (s, 1H), 2.04 (m, 1H),
3
1
.63 (ddd, 2H, J = 4.7 Hz, J = 12.0 Hz, J = 14.0 Hz), 1.33 (m, 9H), 0.89 (t, 3H, J = 6.9
13
Hz); C NMR (CDCl , 125 MHz) δ ppm: 104.4, 83.0, 31.8, 31.5, 29.2, 29.1, 26.1, 22.6,
1
3
+
4.1; HRMS m/z calcd. for C H O [M-CCl ] , 129.1279; found 129.1280.
8 17 3
5
-(tert-Butyldimethylsilyloxy)-1,1,1-trichloropentan-2-ol (2b)
The crude material was purified by flash chromatography through a plug of silica gel,
using 95:5 hexane/EtOAc as the eluant. The indicated compound was obtained as a
-
colorless oil in 93% yield. IR (film): 3580 (b), 3053 (m), 2956 (m), 1265 (s), 739 (s) cm
S 1

1
1
;
H NMR (CDCl , 500 MHz) δ ppm: 4.01 (ddd, 1H, J = 1.8 Hz, J = 5.6 Hz, J = 9.4
3
Hz), 3.66 (m, 2H), 2.87 (m, 1H), 2.08 (m, 1H), 1.64 (m, 5H), 0.90 (s, 9H), 0.06 (s, 6H);
1
3
C NMR (CDCl , 125 MHz) δ ppm: 104.3, 83.1, 63.0, 32.2, 31.2, 26.0, 22.8, 18.4, -5.3;
3
+
HRMS m/z calcd. for C H Cl SiO [M-C H ] , 276.9985; found 276.9977.
8
16
3
2
4
9
1
,1,1-Trichloro-4-phenylbutan-2-ol (2c)
The crude material was purified by flash chromatography through a plug of silica gel,
using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a
-
colorless oil in 89% yield. IR (film): 3439 (b), 3028 (m), 2936 (m), 1265 (m), 746 (s) cm
1
1
;
H NMR (CDCl , 500 MHz) δ ppm: 7.28 (td, 5H, J = 7.4Hz, J = 14.4Hz), 3.99 (ddd,
3
1
H, J = 1.9Hz, J = 5.4Hz, J = 10.0Hz), 3.01 (ddd, 1H, J = 4.8 Hz, J = 9.1 Hz, J = 13.9
Hz), 2.77 (m, 2H), 2.39 (m, 1H), 2.00 (dddd, 1H, J = 4.8 Hz, J = 8.8 Hz, J = 10.0 Hz, J
13
=
13.8 Hz); C NMR (CDCl , 125 MHz) δ ppm: 140.7, 128.6, 128.5, 126.3, 104.1, 82.0,
3
3
2.9, 32.0; HRMS m/z calcd. for C H Cl O, 251.9875; found 251.9885.
10 11 3
2
,2,2-Trichloro-1-cyclohexylethanol (2d)
The crude material was purified by flash chromatography through a plug of silica gel,
using 95:5 hexane/EtOAc as the eluant. The indicated compound was obtained as a
-
colorless oil in 87% yield. IR (film): 3577 (b), 3053 (m), 2986 (m), 1266 (s), 747 (s) cm
1
1
;
H NMR (CDCl , 500 MHz) ꢀ ppm: 3.83 (dd, 1H, J = 6.50, 2.51 Hz), 2.73 (m, 1H),
.04 (m, 2H), 1.70 (m, 4H), 1.32 (m, 4H); C NMR (CDCl , 125 MHz) δ ppm: 104.2,
6.4, 39.9, 32.9, 26.7, 26.5, 26.0, 25.9; HRMS m/z was calcd. for C H O [M-CCl ] ,
3
1
3
2
8
1
3
+
7
13
3
13.0966; found 113.0965.
1
,1,1-Trichloro-3-phenylbutan-2-ol (2e)
The crude material was purified by flash chromatography through a plug of silica gel,
using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a
-1
colorless oil in 90% yield. IR (film): 3577 (b), 3054 (s), 2986 (s), 1265 (s), 748 (s) cm ;
1
H NMR (CDCl , 500 MHz) δ ppm: 7.33 (m, 1H), 7.25 (dd, 1H, J = 2.2 Hz, J = 4.8 Hz),
3
4
1
.29 (dd, 1H, J = 2.6 Hz, J = 5.8 Hz), 4.21 (dd, 1H, J = 3.3 Hz, J = 8.3 Hz), 3.62 (dd,
H, J = 3.3 Hz, J = 7.3 Hz), 3.54 (dd, 1H, J = 2.6 Hz, J = 7.1 Hz), 2.94 (d, 1H, J = 5.8
1
3
Hz), 2.56 (d, 1H, J = 8.3 Hz), 1.52 (d, 1H, J = 7.3 Hz), 1.48 (d, 1H, J = 7.1 Hz); C
NMR (CDCl , 125 MHz) δ ppm: 145.7, 140.3, 129.5, 128.7, 128.4, 127.4, 126.8, 104.0,
3
8
2
5.8, 41.7, 41.1, 21.7, 15.9; HRMS m/z calcd. for C H Cl O, 251.9875; found
51.9872.
10 11 3
1
,1,1-Trichloro-1-phenylethanol (2f)
The crude material was purified by flash chromatography through a plug of silica gel,
using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a
colorless oil in 96% yield. IR (film): 3446 (b), 3055 (m), 2984 (w), 2901 (w), 1265 (s),
-
1 1
6
3
1
97 (s) cm ; H NMR (CDCl , 500 MHz) δ ppm: 7.45 (m, 5H), 5.22 (d, 1H, J = 4.0 Hz),
3
1
3
.27 (d, 1H, J = 4.0 Hz); C NMR (CDCl , 125 MHz) δ ppm: 134.8, 129.5, 129.2, 127.8,
03.1, 84.5; HRMS m/z calcd. for C H Cl O, 223.9562; found 223.9563.
3
8
7
3
2
,2,2-Trichloro-1-(4-methoxyphenyl)ethanol (2g)
S 2

The crude material was purified by flash chromatography through a plug of silica gel,
using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a white
solid in 97% yield; m.p. 44-45°C. IR (solid): 3511 (b), 3019 (w), 2840 (w), 1253 (s),
-
1 1
1
(
175 (s), 740 (s) cm ; H NMR (CDCl , 500 MHz) δ ppm: 7.52 (d, 2H, J = 8.6 Hz), 6.90
3
13
d, 2H, J = 8.9 Hz), 5.16 (d, 1H, J = 3.9 Hz), 3.81 (s, 3H), 3.26 (d, 1H, J = 4.0 Hz); C
NMR (CDCl , 125 MHz) δ ppm: 160.4, 130.4, 126.9, 113.2, 103.5, 84.2, 55.3; HRMS
3
m/z was calcd. for C H OCl , 253.9668; found 253.9665.
9
9
3
2
,2,2-Trichloro-1-(4-nitrophenyl)-ethanol (2h)
The crude material was purified by flash chromatography through a plug of silica gel,
using 8:2 hexane/EtOAc as the eluant. The indicated compound was obtained as a white
solid in 95% yield; m.p. 107-108 °C. IR (film): 3568 (b), 3054 (s), 2986 (m), 1525 (s),
-
1
1
1
8
350 (s), 1265 (s), 747 (s) cm ; H NMR (CDCl , 500 MHz) δ ppm: 8.25 (d, 2H, J =
3
13
.9 Hz), 7.83 (d, 2H, J = 8.7 Hz), 5.34 (d, 1H, J = 3.6 Hz), 3.44 (d, 1H, J = 3.6 Hz); C
NMR (CDCl , 125 MHz) δ ppm: 148.5, 141.3, 130.4, 122.8, 102.0, 83.5; HRMS m/z
3
calcd. for C H Cl NO, 268.9413; found 268.9406.
8
6
3
2
,2,2-Trichloro-1-napthalen-2-yl-ethanol (2i)
The crude material was purified by flash chromatography through a plug of silica gel,
using 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a white
-1
solid in 93% yield; m.p. 93-94 °C. IR (solid): 3486 (b), 3049 (m), 1240 (m), 745 (s) cm ;
1
H NMR (CDCl , 500 MHz) δ ppm: 8.09 (s, 1H), 7.88 (m, 3H), 7.74 (dd, 1H, J = 1.7 Hz,
3
1
3
J = 8.6 Hz), 7.53 (m, 2H), 5.40 (d, 1H, J = 3.9 Hz), 3.37 (d, 1H, J = 4.0 Hz); C NMR
CDCl , 125 MHz) δ ppm: 133.7, 132.5, 132.2, 129.2, 128.4, 127.7, 127.4, 126.8, 126.3,
(
3
1
26.1, 103.2, 84.7; HRMS m/z was calcd. for C H OCl , 273.9712; found 273.9713
12 9 3
2
,2,2-Trichloro-1-furan-2-yl-ethanol (2j)
The crude material was purified by flash chromatography through a plug of silica gel,
using 95:5 hexane/EtOAc as the eluant. The indicated compound was obtained as a
white solid in 95% yield; m.p. 34-35 °C. IR (film): 3431 (b), 2922 (w), 1263 (w), 707 (s)
-
1
1
cm ; H NMR (CDCl , 500 MHz) ꢀ ppm: 7.47 (dd, 1H, J = 0.8 Hz, J = 1.8 Hz), 6.61 (d,
3
1
3
1
H, J = 3.4 Hz), 6.44 (dd, 1H, J = 1.8 Hz, J = 3.3 Hz), 5.24 (s, 1H), 3.33 (s, 1H); C
NMR (CDCl , 125 MHz) δ ppm: 148.4, 143.1, 110.9, 110.7, 101.2, 79.3; HRMS m/z was
3
calcd. for C H Cl O , 213.9355; found 213.9352.
6
5
3
2
2
,2,2-Trichloro-1-thiophen-2-ylethanol (2k)
The crude material was purified by flash chromatography through a plug of silica gel,
using 95:5 hexane/EtOAc as the eluant. The indicated compound was obtained as a
-1
yellow oil in 93% yield. IR (film): 3422 (b), 3060 (w), 2912 (w), 1265 (m), 742 (s) cm ;
1
H NMR (CDCl , 500 MHz) ꢀ ppm: 7.40 (dd, 1H, J = 5.09, 1.20 Hz), 7.31 (ddd, 1H, J =
3
3
1
8
.59, 1.05, 0.59 Hz), 7.05 (dd, 1H, J = 5.08, 3.62 Hz), 5.47 (d, 1H, J = 4.76 Hz), 3.51 (d,
1
3
H, J = 4.83 Hz); C NMR (CDCl , 125 MHz) δ ppm: 137.3, 129.1, 127.1, 126.2, 102.4,
3
1.4; HRMS m/z was calcd. for C H Cl SO, 229.9127; found 229.9122.
6
5
3
1
,1,1-Trichloro-4-methylpent-3-en-2-ol (2l)
S 3

The crude material was purified by flash chromatography through a plug of silica gel,
using 95:5 hexane/EtOAc as eluant. The indicated compound was obtained as a white
o
1
solid in 87% yield; m.p. 85-86 C. H NMR (CDCl , 360 MHz) δ ppm: 5.35 (d, 1H, J =
3
1
3
1
.08 Hz), 4.79 (t, 1H), 2.59 (d, 1H, J = 5.76 Hz), 1.83 (s, 6H); C NMR (CDCl , 90
3
MHz) δ ppm: 142.5, 119.5, 103.6, 79.5, 26.1, 19.2; HRMS m/z calcd. for C H Cl O,
5
9
3
+
2
01.9719; found 85.0652 which corresponds to [M-CCl ] .
3
1
,1,1-Trichlorohex-3-en-2-ol (2m)
The crude material was purified by flash chromatography through a plug of silica, using
9
9
5:5 hexane/EtOAc as eluant. The indicated compound was obtained as a yellow oil in
1
0% yield. H NMR (CDCl , 500 MHz) δ ppm: 6.07 (m, 1H), 5.65 (ddd, 1H, J = 1.6 Hz,
3
J = 6.5 Hz, J = 15.4 Hz), 4.53 (t, 1H, J = 6.1 Hz), 2.73 (t, 1H, J = 6.1 Hz), 2.16 (dd, 2H,
1
3
J = 7.1 Hz, J = 13.9 Hz), 1.05 (dt, 3H, J = 1.3 Hz, J = 7.5 Hz); C NMR (CDCl , 90
3
MHz) δ ppm: 140.9, 122.8, 103.1, 83.5, 25.5, 12.9; HRMS m/z calcd. for C H O, 85.0653
5
9
+
[
M-CCl ] ; found 85.0650.
3
1
,1,1-Trichloro-3-methylhex-3-en-2-ol (2n)
The crude material was purified by flash chromatography through a plug of silica, using
9
8
2
7
5:5 hexane/EtOAc as eluant. The indicated compound was obtained as a colorless oil in
1
6% yield. H NMR (CDCl , 500 MHz) δ ppm: 5.74 (t, 1H, J = 7.0 Hz), 4.55 (d, 1H, J =
3
.7 Hz), 2.89 (d, 1H, J = 4.1 Hz), 2.12 ( m, 2H, J = 7.6 Hz), 1.82 (s, 3H), 1.01 (t, 3H, J =
13
.6 Hz); C NMR (CDCl , 90 MHz) δ ppm: 137.7, 129.1, 87.7, 21.2, 13.4, 13.0; HRMS
3
+
m/z calcd. for C H Cl O, 215.9875; found 214.9803 which corresponds to [M-1] .
7
11
3
S 4

General Procedure for the Preparation of One-Carbon Homologated Carboxylic
Acids from Trichloromethyl Carbinols
Method A:
To a solution of trichloromethyl carbinol (1 mmol) in tert-BuOH (10mL) was added
freshly powdered NaOH (3.3 mmol) at 30 °C. The mixture was stirred rapidly for 10
min, then NaBH (1.5 mmol) was added and the heterogeneous mixture was warmed to
4
3
5 °C or 55 °C with vigorous stirring. The reaction was monitored by TLC after 12 h
(
stain plate with KMnO if necessary), and an additional 0.5 mmol of NaBH was added
4
4
if starting material remained. Once the reaction was completed, (12-48 h in total,
depending on temperature and substrate), the tert-BuOH was removed by rotary
evaporation and the amorphous solids were dissolved in 5 mL diethyl ether and 5 mL
H O. The resulting solution was cooled to 0 °C and adjusted to pH 1 with 1 N HCl (or to
2
pH 4 with KH PO for entry 2j). The product was extracted with diethyl ether (5 × 10
2
4
mL), dried with anhydrous magnesium sulfate, and then concentrated by rotary
evaporation. The crude material was purified by flash chromatography through a small
plug of silica using specified eluants, affording the carboxylic acid.
Method B:
Diphenyl diselenide (1.05 mmol, 328 mg) was added to dry round-bottom flask equipped
with stir bar under a blanket of argon. Deoxygenated absolute ethanol (4 mL) (purged for
3
0 minutes with argon) was then added, followed by the rapid addition of NaBH (2.1
4
mmol, 80 mg) under argon. After the addition of NaBH , the yellow solution turned clear
4
and colorless, and then the reaction stirred at room temperature for 30 minutes. Neat
alkenyl or aryl trichloromethyl carbinol (1 mmol) was quickly added, followed by the
addition of NaOH (6 mmols, 240 mg) under argon. The reaction was heated to 40°C and
then allowed to react at this temperature for 24-36 hours while monitoring by TLC for
consumption of starting material. After completion, ethanol was removed by rotary
evaporation and the amorphous solids were dissolved in 5 mL ethyl acetate and 5mL
H O. The resulting solution was cooled to 0 °C and adjusted to pH 1 with 1 N HCl. The
2
product was extracted with ethyl acetate (5 × 10 mL), dried with anhydrous magnesium
sulfate, and then concentrated by rotary evaporation. The crude material was purified by
flash chromatography through a small plug of silica using specified eluants, affording the
carboxylic acid.
Nonoic acid (5a)
After preparing using Method A, the crude material was purified by flash
chromatography through a plug of silica gel, using 9:1 hexane/EtOAc as the eluant. The
1
indicated compound was obtained as a yellow oil in 94% yield. H NMR (CDCl , 500
3
MHz) ꢀ ppm: 9.98 (s, 1H), 2.34 (t, 2H, J = 7.52, 7.52 Hz), 1.62 (td, 2H, J = 14.87, 7.44,
13
7
.44 Hz), 1.28 (m, 10H), 0.87 (t, 3H, J = 6.81, 6.81 Hz); C NMR (CDCl , 125 MHz) δ
3
ppm: 180.2, 34.1, 31.8, 29.2, 29.1, 29.1, 24.7, 22.6, 14.1; HRMS m/z was calcd. for
C H O , 158.1312; found 158.1307.
9
18
2
6
-(tert-Butyldimethylsilyloxy)hexanoic acid (5b)
S 5

After preparing using Method A, the crude material was purified by flash
chromatography through a plug of silica gel, using 9:1 hexane/EtOAc as the eluant. The
1
indicated compound was obtained as a colorless oil in 89% yield. H NMR (CDCl , 500
3
MHz) ꢀ ppm: 3.61 (t, 2H, J = 6.62, 6.31 Hz), 2.36 (t, 2H, J = 7.57, 7.57 Hz), 1.66 (m,
1
3
2
H), 1.53 (m, 2H), 1.39 (m, 2H), 0.89 (s, 9H), 0.04 (s, 6H); C NMR (CDCl , 125 MHz)
3
δ ppm: 178.8, 62.9, 33.8, 32.4, 26.0, 24.5, 18.3, -5.3; HRMS m/z was calcd. for
+
C H SiO [M-C H ] , 189.0950; found 189.0949.
8
17
3
4
9
4
-Phenylbutanoic acid (5c)
After preparing using Method A, the crude material was purified by flash
chromatography through a plug of silica gel, using 85:15 hexane/EtOAc as the eluant.
The indicated compound was obtained as colorless crystals in 93% yield; m.p. 50-51 °C.
1
H NMR (CDCl , 500 MHz) ꢀ ppm: 10.70 (s, 1H), 7.29 (t, 2H, J = 7.44, 7.44 Hz), 7.20
3
(t, 3H, J = 8.37, 8.37 Hz), 2.68 (t, 2H, J = 7.60, 7.60 Hz), 2.39 (t, 2H, J = 7.44, 7.44 Hz),
1
3
1
3
.98 (m, 2H); C NMR (CDCl , 125 MHz) δ ppm: 179.5, 141.2, 128.5, 128.4, 126.0,
3
5.0, 33.3, 26.2; HRMS m/z was calcd. for C H O , 164.0842; found 164.0837.
1
0
12
2
Cyclohexylacetic acid (5d)
After preparing using Method A, the crude material was purified by flash
chromatography through a plug of silica gel, using 9:1 hexane/EtOAc as the eluant. The
1
indicated compound was obtained as a colorless oil in 85% yield. H NMR (CDCl , 500
3
MHz) ꢀ ppm: 11.06 (s, 1H), 2.23 (d, 2H, J = 6.21Hz), 1.77 (m, 6H), 1.26 (m, 4H), 0.98
1
3
(
m, 1H); C NMR (CDCl , 125 MHz) δ ppm: 178.7, 41.7, 34.7, 33.0, 26.1, 26.0; HRMS
3
m/z was calcd. for C H O , 142.0990; found 142.0994.
8
14
2
3
-Phenylbutyric acid (5e)
After preparing using Method A, the crude material was purified by flash
chromatography through a plug of silica gel, using 85:15 hexane/EtOAc as the eluant.
1
The indicated compound was obtained as a colorless oil in 85% yield. H NMR (CDCl ,
3
5
1
00 MHz) ꢀ ppm: 7.31 (m, 2H), 7.23 (dd, 3H, J = 7.78, 3.25 Hz), 3.28 (dd, 2H, J =
4.73, 7.12 Hz), 2.64 (ddd, 1H, J = 23.74, 15.52, 7.51 Hz), 1.33 (d, 3H, J = 6.98 Hz); C
1
3
NMR (CDCl , 125 MHz) δ ppm: 177.9, 145.5, 128.6, 126.7, 42.5, 36.2, 21.8; HRMS m/z
3
was calcd. for C H O , 164.0830; found 164.0837.
1
0
12
2
Phenylacetic acid (5f)
After preparing using Method A, the crude material was purified by flash
chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide
then 85:15 hexane/EtOAc as the eluant. The indicated compound was obtained as
1
colorless crystals in 92% yield; m.p. 77-78 °C. H NMR (CDCl , 500 MHz) ꢀ ppm:
3
1
3
1
1
1
1.78 (s, 1H), 7.32 (m, 5H), 3.66 (s, 2H); C NMR (CDCl , 125 MHz) δ ppm: 178.1,
33.2, 129.3, 128.6, 127.3, 41.1; HRMS m/z was calcd. for C H O , 136.0527; found
3
8
8
2
36.0524.
4-Methoxyphenyl)acetic acid (5g)
(
After preparing using Method B, the crude material was purified by flash
chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide
S 6

then 8:2 hexane/EtOAc as the eluant. The indicated compound was obtained as a white
1
solid in 92% yield; m.p. 85-86 °C. H NMR (CDCl , 360 MHz) δ ppm: 7.20 (d, 2H, J =
3
1
3
8
.7 Hz), 6.87 (d, 2H, J = 8.7 Hz), 3.59 (s, 3H), 3.80 (s, 2H); C NMR (CDCl , 125
3
MHz) δ ppm: 177.3, 158.9, 130.4, 125.3, 114.1, 55.3, 40.0; HRMS m/z calcd. for
C H O 166.0630; found 166.0634.
9
10 3,
4
-Nitrophenyl acetic acid (5h)
After preparing using Method B, the crude material was purified by flash
chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide
then 1:1 hexane/EtOAc with 1% AcOH as the eluant. The indicated compound was
1
obtained as a white solid in 85% yield; m.p. 154-155 °C. H NMR (CD COCD , 500
3
3
1
3
MHz) ꢀ ppm: 8.19 (d, 2H, J = 8.6 Hz) ppm 7.58 (d, 2H, J = 8.5 Hz) ppm 3.77 (s, 2H); C
NMR (CD COCD , 125 MHz) δ ppm: 171.672, 148.261, 143.537, 131.766, 124.456,
3
3
4
1.351; HRMS m/z was calcd. for C H NO , 181.0377; found 181.0375.
8 7 4
Naphthalen-2-ylacetic acid (5i)
After preparing using Method B, the crude material was purified by flash
chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide
then 8:2 hexane/EtOAc as the eluant. The indicated compound was obtained as a white
1
solid in 94% yield; m.p. 142-143 °C. H NMR (CDCl , 500 MHz) δ ppm: 11.00 (s, 1H),
3
7
.81 (t, 3H, J = 9.1 Hz), 7.74 (s, 1H), 7.47 (m, 2H), 7.41 (dd, 1H, J = 1.8 Hz, J = 8.4
1
3
Hz), 3.82 (s, 2H); C NMR (CDCl , 125 MHz) δ ppm: 177.4, 133.4, 132.6, 130.7,
3
1
1
28.3, 128.2, 127.7, 127.7, 127.3, 126.2, 125.9, 41.1; HRMS m/z calcd. for C H O ,
86.0681; found 186.0683.
12 10 2
2
-(Furan-2-yl)acetic acid (5j)
After preparing using Method B, the crude material was purified by flash
chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide
then 85:15 hexane/EtOAc as the eluant. The indicated compound was obtained as a
1
white solid in 92% yield; m.p. 60-61°C . H NMR (CDCl , 500 MHz) ꢀ ppm: 10.96 (s,
3
1
3
1
H), 7.40 (dd, 1H, J = 1.79, 0.72 Hz), 6.37 (dd, 1H, J = 3.15, 1.90 Hz), 6.28 (dd, 1H, J =
.21, 0.64 Hz), 3.77 (s, 2H); C NMR (CDCl , 125 MHz) δ ppm: 173.7, 146.9, 142.3,
10.6, 108.4, 33.5; HRMS m/z was calcd. for C H O , 126.0321; found 126.0317.
1
3
3
6
6
3
2
-(Thiophen-2-yl)acetic acid (5k)
After preparing using Method B, the crude material was purified by flash
chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide
then 85:15 hexane/EtOAc as the eluant. The indicated compound was obtained as a gray
1
solid in 94% yield; m.p. 64-65 °C. H NMR (CDCl , 500 MHz) ꢀ ppm: 11.16 (s, 1H),
3
1
3
7
.24 (dd, 1H, J = 4.52, 1.87 Hz), 6.98 (dd, 1H, J = 5.47, 2.55 Hz), 3.89 (s, 1H); C
NMR (CDCl , 125 MHz) δ ppm: 176.4, 134.0, 127.3, 126.9, 125.3, 35.0; HRMS m/z was
3
calcd. for C H SO , 142.0092; found 142.0089.
6
6
2
4
-Methylpent-3-enoic acid (5l)
After preparing using Method B, the crude material was purified by flash
chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide
S 7

then 9:1 hexane/EtOAc as the eluant. The indicated product was obtained as a yellow oil
1
in 95% yield. H NMR (CDCl , 360 MHz) δ ppm: 5.30 (tddd, 1H, J = 1.4 Hz, J = 2.8
3
Hz, J = 5.7 Hz, J = 8.5 Hz), 3.07 (d, 2H, J = 7.2 Hz), 1.75 (d, 3H, J = 1.1 Hz), 1.64 (s,
1
3
3
H); C NMR (CDCl , 360 MHz) δ ppm: 178.7, 136.3, 115.0, 33.5, 25.6, 17.9; HRMS
3
m/z calcd. for C H O , 114.0681; found 114.0681.
6
10
2
(E)-Hex-3-enoic acid (5m)
After preparing using Method B, the crude material was purified by flash
chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide
then 9:1 hexane/EtOAc as the eluant. The indicated compound was obtained as a yellow
1
oil in 95% yield. H NMR (CDCl , 360 MHz) δ ppm: 5.64 (ddd, 1H, J = 6.1 Hz, J = 11.8
3
Hz, J = 12.3 Hz), 5.51 (ddd, 1H, J = 6.1 Hz, J = 11.8 Hz, J = 12.3 Hz), 3.07 (dd, 2H, J =
1
7
.1 Hz, J = 6.8 Hz), 2.07 (ddd, 2H, J = 3.8 Hz, J = 6.9 Hz, J = 7.4 Hz), 0.98 (d, 3H, J =
13
.5 Hz); C NMR (CDCl , 360 MHz) δ ppm: 178.5, 137.0, 119.8, 37.7, 25.5, 13.4;
3
HRMS m/z calcd. for C H O , 114.0681; found 114.0676.
6
10
2
(E)-3-Methylhex-3-enoic acid (5n)
After preparing using Method B, the crude material was purified by flash
chromatography through a plug of silica gel, using hexane to remove diphenyldiselenide
then 9:1 hexane/EtOAc as the eluant. The indicated product was obtained as a yellow oil
1
in 87% yield. H NMR (CDCl , 360 MHz) δ ppm: 5.31 (dd, 1H, J = 7.0 Hz, J = 8.1 Hz),
3
3
1
3
.02 (s, 2H), 2.04 ( p, 2H, J = 7.2 Hz), 1.70 (s, 3H), 0.96 (t, 3H, J = 7.6 Hz); C NMR
(
CDCl , 360 MHz) δ ppm: 178.7, 131.9, 127.0, 44.7, 21.3, 16.0, 13.9; HRMS m/z calcd.
3
for C H O , 128.0837; found 128.0838.
7
12
2
Preparation of (S)-2-tert-Butoxycarbonylamino-3-phenylpropanaldehyde (20).
Protected (S)-amino aldehyde 20 was prepared by the method of Myers and co-workers.
The indicated crude product was obtained as a white solid in quantitative yield after
work-up. Sensitive aldehyde 20 was used in the next step without purification.
3
Preparation
of
tert-Butyl
(2S)-4,4,4-trichloro-3-hydroxy-1-phenylbutan-2-yl
carbamate. To a solution of sodium trichloroacetate (245 mg, 1.5 mmol) and
trichloroacetic acid (278 mg, 1.5 mmol) in 2 mL of DMF was added 20 (249 mg, 1
mmol) in 1 mL DMF with stirring at 0°C. After 15 min., warm the reaction mixture to
room temperature. After 12 h, the mixture was diluted with 5 mL of diethyl ether and
washed with saturated aqueous sodium bicarbonate solution. Precipitated solids were
filtered and washed three times with diethyl ether. The filtrate was washed two more
times with the sodium bicarbonate solution and once with brine. The organic phase was
dried with sodium sulfate and the diethyl ether was evaporated under reduced pressure.
The crude material was purified by flash chromatography through a plug of silica gel,
using 8:2 hexane/EtOAc as eluant. The indicated compound was obtained as a white solid
in 91% yield (335 mg, 0.91 mmol); m.p. 147-148°C. IR (film): 3579 (w), 3439 (b), 3054
-1 1
(
m), 2985 (m), 1709 (m), 1265 (s), 1166 (m), 739 (s) cm ; H NMR (CDCl , 500 MHz) δ
3
ppm: 7.30 (m, 3H), 7.27 (m, 2H), 5.04 (m, 2H), 4.38 (m, 1H), 4.03 (d, 1H, J = 7.0 Hz),
13
3
.18 (m, 1H), 2.94 (m, 1H), 1.41 (s, 9H); C NMR (CDCl , 90 MHz) δ ppm: 156.2,
3
S 8

1
37.3, 129.4, 128.6, 126.8, 102.2, 81.3, 80.2, 52.6, 39.7, 28.3; HRMS m/z calcd. for
+
C H Cl NO [M-C H ] , 310.9878; found 310.9878.
15
20
3
3
4
9
Preparation of (S)-3-tert-Butoxycarbonylamino-4-phenylbutyric acid methyl ester
21) by Method A. To a solution of (2S)-4,4,4-trichloro-3-hydroxy-1-phenylbutan-2-yl
(
carbamate (170 mg, 0.46 mmol) in tert-BuOH (4.6 mL) was added freshly powdered
NaOH (61 mg, 1.52 mmol) at 30 °C. The mixture was stirred rapidly for 10 min, then
NaBH (26 mg, 0.69 mmol) was added and the heterogeneous mixture was warmed to 55
4
°
C with vigorous stirring. The reaction was monitored by TLC after 12 h, and an
additional 0.5 mmol of NaBH was added to achieve full conversion. Once the reaction
4
was completed (24 h in total) the tert-BuOH was removed by rotary evaporation and the
amorphous solids were dissolved in 3 mL of THF. Dimethyl sulfate (0.87 mL, 9.2 mmol)
was added and the reaction was stirred at room temperature for 24 h. The THF was
removed by rotary evaporation and the amorphous solids were dissolved in 5 mL of ethyl
acetate. The resulting solution was cooled to 0°C and 5 mL of a 50% aqueous solution of
ammonium hydroxide was added. After 1 hour of stirring at 0°C, the solution was
allowed to warm to room temperature. The product was extracted with ethyl acetate (5 ×
1
0 mL), dried with anhydrous magnesium sulfate, and then concentrated by rotary
evaporation. The crude material was purified by flash chromatography through a plug of
silica gel, using hexane to remove diphenyldiselenide then 97:3 hexane/EtOAc as the
eluant. The ꢀ-amino ester 21 was obtained as a colorless amorphous solid in 70% yield
(90 mg, 0.32 mmol).
Preparation of (S)-3-tert-Butoxycarbonylamino-4-phenylbutyric acid methyl ester
21) by Method B. Diphenyl diselenide (0.96 mmol, 300 mg) was added to dry round-
(
bottom flask equipped with stir bar under a blanket of argon. Deoxygenated absolute
ethanol (3.7 mL, purged for 30 minutes with argon) was then added, followed by the
rapid addition of NaBH (1.9 mmol, 73 mg) under argon. After the addition of NaBH ,
4
4
the yellow solution turned clear and colorless, and then the reaction was stirred at room
temperature for an additional 30 minutes. Neat (2S)-4,4,4-trichloro-3-hydroxy-1-
phenylbutan-2-yl carbamate (0.91 mmol, 335 mg) was added, followed by the addition of
NaOH (5.46 mmols, 218 mg). The reaction was heated to 40°C and then allowed to react
at this temperature for 33 hours while monitoring by TLC for complete conversion. After
completion, ethanol was removed by rotary evaporation and the amorphous solids were
dissolved in 5 mL of THF. Dimethyl sulfate (18.2 mmol, 1.73 mL) was added and the
reaction was stirred at room temperature for 24 hours. The THF was removed by rotary
evaporation and the amorphous solids were dissolved in 5 mL of ethyl acetate. The
resulting solution was cooled to 0°C and 5 mL of a 50% aqueous solution of ammonium
hydroxide was added. After 1 hour of stirring at 0°C, the solution was allowed to warm to
room temperature. The product was extracted with ethyl acetate (5 × 10 mL), dried with
anhydrous magnesium sulfate, and then concentrated by rotary evaporation. The crude
material was purified by flash chromatography through a plug of silica gel, using hexane
to remove diphenyldiselenide then 97:3 hexane/EtOAc as the eluant. The ꢀ-amino ester
2
4
2
1 was obtained as a colorless amorphous solid in 83% yield (243 mg, 0.83 mmol). [ꢀ]
D
4
-19.8 (c 1.11, MeOH) ; IR (film): 3582 (w), 3054 (m), 2983 (m), 1774 (s), 1669 (m),
1
1
111 (s); H NMR (CDCl , 500 MHz) δ ppm: 7.28 (m, 5H), 5.06 (m, 1H), 4.19 (m, 1H),
3
S 9

1
3
3
.71 (s, 3H), 2.85 (m, 2H), 2.52 (dd, 2H, J = 5.4 Hz, J = 19.5 Hz), 1.43 (s, 9H); C
NMR (CDCl , 360 MHz) δ ppm: 172.1, 155.1, 137.7, 129.4, 128.5, 126.6, 79.3, 51.6,
3
4
8.8, 40.4, 40.3, 37.6, 28.3; HRMS m/z calcd. for C H NO , 293.1636; found 293.1632.
16 23 4
Preparation of (S)-4-Phenyl-3-((R)-3,3,3-trifluoro-2-methoxy-2-
phenylpropionylamino)butyric acid methyl ester.
(S)-4-Phenyl-3-((R)-3,3,3-trifluoro-2-methoxy-2-phenylpropionylamino)butyric acid
methyl ester was prepared by the method of Mazaleyrat and co-workers and then
1
13
19
5 1
analyzed by H, C, and F NMR spectroscopy. H NMR (CDCl , 500 MHz) δ ppm:
3
7
.39 (m, 8H), 7.206 (m, 3H), 4.52 (m, 1H), 3.62 (s, 3H), 3.27 (d, 3H, J = 1.26 Hz), 2.95
1
3
(dd, 2H, J = 7.57 Hz, J = 5.99 Hz), 2.54 (m, 2H); C NMR (CDCl , 500 MHz) δ ppm:
3
1
4
71.7, 165.8, 137.1, 132.6, 129.4, 129.3, 128.7, 128.5, 127.6, 126.8, 124.9, 54.8, 51.7,
1
9
7.8, 39.7, 36.9; F NMR (CDCl , 360 MHz) δ ppm: -68.9.
3
Preparation of 4-Phenyl-2-deuterobutyric acid (22). To a solution of trichloromethyl
carbinol (2c) (252 mg, 1 mmol) in tert-BuOH (10mL) was added freshly powdered
NaOH (132 mg, 3.3 mmol) at 30 °C. The mixture was stirred rapidly for 10 min, then
NaBD (63 mg, 1.5 mmol) was added and the heterogeneous mixture was warmed to 55
4
°
C with vigorous stirring. The reaction was monitored by TLC after 12 h (stain plate
with KMnO if necessary), and an additional 0.5 mmol of NaBD (21mg, 0.5 mmol) was
4
4
added. Once the reaction was completed, (24 h in total), the tert-BuOH was removed by
rotary evaporation and the amorphous solids were dissolved in 5 mL diethyl ether and 5
mL H O. The resulting solution was cooled to 0 °C and adjusted to pH 1 with 1 N HCl.
2
The product was extracted with diethyl ether (5 × 10 mL), dried with anhydrous
magnesium sulfate, and then concentrated by rotary evaporation. The crude material was
purified by flash chromatography through a plug of silica gel, using 97:3 hexane/EtOAc
as the eluant. The indicated product was obtained as a colorless oil in 87 % yield (144
1
mg, 0.87 mmol). H NMR (CDCl , 500 MHz) δ ppm: 11.16 (s, 1H), 7.29 (m, 1H), 7.20
(
3
13
m, 1H), 2.69 (m, 1H), 2.37 (m, 1H), 1.98 (dd, 1H, J = 7.5 Hz, J = 15.1 Hz); C NMR
(
CDCl , 360 MHz) δ ppm: 179.1, 141.2, 128.5, 128.4, 126.1, 77.3, 77.0, 76.7, 35.0, 33.1,
3
3
3.0, 32.8, 26.1; HRMS m/z calcd. for C H DO , 165.0900; found 165.0899.
1
0
11
2
S10

References
1
2
3
) Corey, E. J.; Link, J. O.; Shao, Y. Tetrahedron Lett. 1992, 33, 3435.
) Wyvratt, J. M.; Hazen, G. G.; Weinstock, L. M. J. Org. Chem. 1987, 52, 944.
) Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman, B. A.; Kwon, S.
Tetrahedron Lett. 2000, 41, 1359.
4
5
) Gordon, E. M.; Godfrey, J. D.; Delaney, N. G.; Asaad, M. M.; Von Langen, D.;
Cushman, D. W. J. Med. Chem. 1988, 31, 2199.
) Mazaleyrat, J. –P.; Gaucher, A.; Dutot, L.; Barbeau, O.; Hamchaoui, W.; Wakselman,
M. Tetrahedron: Asymmetry 2005, 16, 857.
S11

OH
CCl3
2a
S12

OH
CCl3
2a
S13

O
CCl3
OH
Si
2b
S14

O
CCl3
OH
Si
2b
S15

OH
CCl3
2c
S16

OH
CCl3
2c
S17

OH
CCl3
2d
S18

OH
CCl3
2d
S19

CCl3
OH
2e
S20

CCl3
OH
2e
S21

OH
CCl3
2f
S22

OH
CCl3
2f
S23

OH
CCl3
H CO
3
2g
S24

OH
CCl3
H CO
3
2g
S25

OH
CCl3
O N
2
2h
S26

OH
CCl3
O N
2
2h
S27

OH
CCl3
2i
S28

OH
CCl3
2i
S29