Stereoselective synthesis of fluoroalkylated butanolides

Article abstract of DOI:10.1055/s-0033-1339755

Starting from fluoroalkylated, optically active acyl oxazolidinones the corresponding di- and trisubstituted butanolides were prepared in enantiomerically pure form. Using a divergent synthetic route highly functionalized fluoroalkylated building blocks are accessible. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339755

Accounts and
Rapid Communications in
Synthetic Organic Chemistry
SYNLETT
SUPPORTING INFORMATION
Supporting Information
for DOI: 10.1055/s-0033-1339755
Georg Thieme Verlag KG Stuttgart · New York 2013
©
Thieme

Stereoselective Synthesis of Fluoroalkylated Butanolides
Holger Erdbrink, Constantin Czekelius*
Institute for Chemistry and Biochemistry
Freie Universität Berlin
Takustr. 3, 14195 Berlin, Germany
E-mail: cczekeli@chemie.fu-berlin.de
Supporting Information

General Procedures:
All syntheses involving air- and moisture-sensitive compounds were carried out using
standard Schlenk-type glassware (or in a glove box) under an atmosphere of argon. Solvents
were dried with the solvent purification system MB-SPS 800 from M. Braun or predistilled
according to standard laboratory methods. Unless stated otherwise all chemicals were
purchased from Acros or Aldrich and used without further purification.
1
13
19
The following instruments were used for characterization of the compounds: H, C, and F
NMR spectra were recorded at room temperature using a Bruker AC 250, JEOL ECX 400,
1
13
JEOL Eclipse 500, or Bruker Advance 3 (700 MHz). H NMR and C NMR: chemical shift δ
1
13
are referenced against the residual solvent signal (CDCl , δ H = 7.26 ppm, C = 77.0 ppm,
3
1
13
1
13
(
CD ) CO, δ H = 2.05 ppm, C = 29.84 ppm; MeOD, δ H = 3.31 ppm, C = 49.0 ppm).
3 2
19
F NMR: chemical shift δ is given relative to CFCl (external reference). The order of citation
3
in parentheses is a) multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,
br = broad), b) coupling constants, c) number of protons and d) assignment. Coupling
constants (J) are reported in Hertz (Hz). The attributions of the chemical shifts were
determined by means of COSY and HMQC. Melting points (mp) were determined using a
Büchi 510 apparatus and are uncorrected. High resolution mass spectra (HRMS) were
determined on an Agilent 6210 ESIǦTOF MS instrument with a flow rate of 4 μL/min, spray
voltage 4 kV, and the desolvation gas set to 15 psi. All other parameters were optimized for
+
+
maximal abundance of [M+H] or [M+Na] . IR spectra were recorded using a Jasco 6200
FTIR spectrometer. The specific rotation of optically active compounds was determined with
a 241 Perkin-Elmer polarimeter using a cell with 10.0 cm length and a capacity of 1 mL.
Measurements were performed at room temperature using a Na-lamp with a wavelength of λ
=
589.3 nm. All reactions were monitored by thinǦlayer chromatography (TLC) using Merck
silica gel 60 F254 (0.25 mm thickness). Flash chromatography was carried out using Merck
silica gel 60 (0.040−0.063 mm).
2

Synthesis of Fluoroalkylated γ-Butyrolactones
(
S)-4-Benzyl-3-{(S)-2-[(R)-1,1,1-trifluorobutan-2-yl]pent-4-enoyl}oxazolidin-2-one (4)
A solution of NaHMDS (2 M in THF, 0.761 mL, 1.52 mmol) was diluted with THF (5.0 mL)
[
1]
and a solution of 3 (334 mg, 1.01 mmol) in THF (5.0 mL) was slowly added at -78 °C. The
resulting mixture was stirred for 1 h at that temperature. A solution of allyl iodide (464 μL,
5.08 mmol) in THF (3.0 mL) was added dropwise. The reaction mixture was stirred at -40 °C
for 5 h and then allowed to warm to rt overnight. Water (7 mL) was added and the aqueous
layer was extracted with diethyl ether (4 x 7 mL). The combined organic phases were
washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude
19
product (dr = 82:18, F NMR) was purified by flash column chromatography (SiO , ethyl
2
acetate/hexane 1:9) to afford 161 mg (43%, 0.436 mmol) of 4 as colorless oil and 18.0 mg
(
4.8%, 0.049 mmol) of a mixture of 4/2-epi-4 as a light yellow oil.
22
1
[
α]D = +44.2 (c = 1.00, CHCl ); H NMR (500 MHz, CDCl ): δ = 1.05 (t, J = 7.6 Hz, 3 H,
3 3
CH CH ), 1.69-1.76 (m, 2 H CH CH ), 2.42-2.47 (m, 1 H, CH CH=CH ), 2.51-2.58 (m, 1 H,
2
3
2
3
2
2
*
*
CHCF ), 2.60-2.66 (m, 1 H, CH CH=CH ), 2.67 (dd, J = 10.1, 13.3 Hz, 1 H, CH Ph), 3.31
3
2
2
2
(
dd, J = 3.3, 13.3 Hz, 1 H, CH Ph), 4.12-4.19 (m, 2 H, OCH ), 4.34 (ddd, J = 4.7, 6.2, 9.7 Hz,
2 2
1
H, COCH), 4.63-4.68 (m, 1 H, NCH), 5.09-5.16 (m, 2 H, CH CH=CH ), 5.78-5.87 (m, 1 H,
2 2
*
13
CH CH=CH ), 7.22-7.35 (m, 5 H, Ph) ppm; signal overlap; C NMR (126 MHz, CDCl ): δ =
2
2
3
1
2.0 (CH CH ), 19.9 (q, J = 2.4 Hz, CH CH ), 33.4 (CH CH=CH ), 37.8 (CH Ph), 41.0 (m ,
2 3 CF 2 3 2 2 2 c
COCH), 45.6 (q, JCF = 24.7 Hz, CHCF ), 55.9 (NCH), 66.0 (OCH ), 118.0 (CH CH=CH )
3
2
2
2
1
27.3 (para-Ar-C), 127.9 (q, JCF = 282 Hz, CF ) 128.9 (ortho-Ar-C), 129.4 (meta-Ar-C), 134.4
3
19
(
Ar-C), 135.2 (CH CH=CH ), 152.9 (OCON), 172.9 (NCOCH) ppm; F NMR (376 MHz,
2 2
CDCl ): δ = -65.6 (d, J = 9.4 Hz, 3 F, CF ) ppm; IR (Film): = 702, 746, 923, 1050, 1107,
3
3
-1
1
170, 1252, 1350, 1366, 1387, 1701, 1781, 2887, 2944, 2978 cm ; HRMS (ESI): m/z
+
+
[
M+Na] calcd. for [C H F NNaO ] : 392.1444; found: 392.1445.
19 22 3 3
(
S)-4-Benzyl-3-{(S)-2-[(R)-1,1,1-trifluoropropan-2-yl]pent-4-enoyl}oxazolidin-2-one (7)
A solution of NaHMDS (2 M in THF, 0.987 mL, 1.97 mmol) was diluted with THF (7.0 mL)
[
1]
and a solution of 6 (415 mg, 1.32 mmol) in THF (7.0 mL) was slowly added at -78 °C. The
3

resulting mixture was stirred for 1 h at that temperature. A solution of allyl bromide (558 μL,
.58 mmol) in THF (4.0 mL) was added dropwise. The reaction mixture was stirred at -40 °C
6
for 4 h and then allowed to warm to rt overnight. Water (7 mL) was added and the aqueous
layer was extracted with diethyl ether (4 x 10 mL). The combined organic phases were
washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude
1
product (dr = 81:19, H NMR) was purified by flash column chromatography (SiO , ethyl
2
acetate/hexane 2:11) to afford 236 mg (50%, 0.664 mmol) of 7 as colorless oil.
22
1
[
α]D = +37.8 (c = 1.01, CHCl ); H NMR (500 MHz, CDCl ): δ = 1.24 (d, J = 7.1 Hz, 3 H,
3 3
*
*
CH ), 2.44-2.51 (m, 1 H, CH CH=CH ), 2.57-2.65 (m, 2 H, CH CH=CH , CHCH ), 2.65
3
2
2
2
2
3
(
dd, J = 10.2, 13.3 Hz, 1 H, CH Ph), 3.31 (dd, J = 3.3, 13.3 Hz, 1 H, CH Ph), 4.14-4.15 (m,
2 2
2
H, OCH ), 4.43 (m , 1 H, COCH), 4.63-4.68 (m, 1 H, NCH), 5.09-5.17 (m, 2 H,
2 c
*
CH CH=CH ), 5.81 (m , 1 H, CH CH=CH ), 7.22-7.35 (m, 5 H, Ph) ppm; signal overlap;
2
2
c
2
2
13
C NMR (126 MHz, CDCl ): δ = 10.8 (q, J = 3.0 Hz, CH ), 34.7 (CH CH=CH ), 37.8
3
CF
3
2
2
(
(
CH Ph), 39.9 (q, J = 26.4 Hz, CHCH ), 40.8 (m , COCH), 55.9 (NCH), 65.9 (OCH ), 118.4
2 CF 3 c 2
CH CH=CH ), 127.3 (para-Ar-C), 127.5 (q, J ~ 279 Hz, CF ), 128.9 (ortho-Ar-C), 129.4
2
2
CF
3
(
meta-Ar-C), 133.9 (Ar-C), 135.3 (CH CH=CH ), 153.0 (OCON), 173.0 (NCOCH) ppm;
2 2
19
F NMR (376 MHz, CDCl ): δ = -69.1 (d, J = 9.3 Hz, 3 F, CF ) ppm; IR (Film): = 702, 747,
3
3
-1
9
23, 1105, 1132, 1173, 1210, 1257, 1351, 1387, 1699, 1783, 2925, 2981cm ; HRMS (ESI):
+
+
m/z [M+Na] calcd. for [C H F NNaO ] : 378.1288; found: 378.1293.
18
20
3
3
(
S)-3-[(R)-1,1,1-Trifluorobutan-2-yl]dihydrofuran-2(3H)-one (5)
A solution of 4 (125 mg, 0.338 mmol) in dichloromethane (6.0 mL) was treated with ozone at
78 °C for 20 min (laboratory ozonator using commercial grade oxygen as source [6.00 V,
.130 mA, 15 cc/min]). The intense blue solution was then flushed with nitrogen for 15 min at
-
0
-
78 °C and a solution of triphenylphosphane (97.0 mg, 0.370 mmol) in dichloromethane
1.0 mL) was added. The mixture was stirred at -78 °C for 30 min. The solution was allowed
(
to warm to rt and stirring was continued for 2 h. The mixture was concentrated and diluted
with dichloromethane (1.0 mL). The solution was triturated with hexane and the phosphine
oxide was filtered off. The solution was concentrated on the rotary evaporator (40 °C,
~250 mbar) to afford 150 mg (quant.) of the aldehyde that was used directly in the next step.
The aldehyde obtained from ozonolysis of 4 was dissolved in diethylether (2.0 mL) and was
4

[2]
added to a stirred suspension of NaBH on alumina (326 mg, ~0.816-0.978 mmol) in Et O
4
2
(
2.0 mL) at rt. Stirring was continued for 15 min, the solid was then filtered off and washed
with diethylether. The solution was concentrated on the rotary evaporator (40 °C,
250 mbar). The crude product was purified by flash column chromatography (SiO2,
diethylether/pentane 1:2) to afford 27.3 mg (41%, 0.139 mmol) of 5 as a colorless oil.
~
22
1
[
α]D = +7.08 (c = 0.50, CHCl ); H NMR (500 MHz, CDCl ): δ = 1.04 (t, J = 7.5 Hz, 3 H,
3 3
CH CH ), 1.37-1.43 (m, 1 H, CH CH ), 1.69-1.78 (m, 1 H, CH CH ) 2.18-2.33 (m, 2 H,
2
3
2
3
2
3
CH CH O), 2.75-2.83 (m, 1 H, CHCF ), 2.99 (ddd, J = 11.8, 9.1, 2.4 Hz, 1 H, COCH), 4.22
2
2
3
13
(
ddd, J = 6.6, 8.9, 10.8 Hz, 1 H, CH CH O), 4.43 (m , 1 H, CH CH O) ppm; C NMR (126
2 2 c 2 2
MHz, CDCl ): δ = 12.5 (CH CH ), 18.3 (q, J = 1.9 Hz, CH CH ), 23.4 (CH CH O), 39.0 (q,
3
2
3
CF
2
3
2
2
JCF = 2.7Hz, COCH), 43.3 (q, JCF = 26.0 Hz, CHCF ), 66.6 (CH CH O) ppm; signals for CF
3
3
2
2
19
and OCCH were not found; F NMR (376 MHz, CDCl ): δ = -69.4 (d, J = 9.2 Hz, 3 F, CF )
3
3
ppm; IR (Film):
= 952, 1024, 1058, 1108, 1175, 1256, 1378, 1770, 2328, 2363, 2923
-1
+
+
cm ;HRMS (ESI): m/z [M+Na] calcd. for [C H F NaO ] : 219.0603; found: 219.0598.
8
11
3
2
(
3S,5S)-5-(Hydroxymethyl)-3-[(R)-1,1,1-trifluoropropan-2-yl]dihydrofuran-2(3H)-one (8a)
and (3S,5R)-5-(Hydroxymethyl)-3-[(R)-1,1,1-trifluoropropan-2-yl]dihydrofuran-2(3H)-one
8b)
(
Following the typical procedure, a solution of 7 (125 mg, 0.352 mmol, dissolved in 0.7 mL
acetone/water 8:1), K OsO ·2H O (10.3 mg, 28.1 μmol, 8 mol%), and N-methylmorpholine-N-
2
4
2
oxide (82.2 mg, 0.702 mmol) in acetone/water 8:1 (1.8 mL) was stirred at rt for 17 h. After
1
work-up, the crude product (dr = 60:40, H NMR) was purified by flash column
chromatography (SiO2, dichloromethane/methanol 97:3) to afford 46.0 mg (61%,
0
.217 mmol) of 8 as a colorless oil.
5

i
The diastereoisomers were separated by HPLC (7.0% PrOH/hexane; flow: 2.0 mL/min,
32 x 250 mm, Nucleosil 50-5, Machery-Nagel) and obtained as colorless oils.
22
1
(
8a) [α]D = +22.3 (c = 1.00, CHCl ); H NMR (500 MHz, CDCl ): δ = 1.33 (d, J = 7.1 Hz, 3 H,
3 3
CH ), 2.27-2.42 (m, 3 H, CH CHCH OH, CH CHCH OH), 2.70-2.79 (m, 1 H, CHCH ), 2.88-
3
2
2
2
2
3
2
1
.93 (m, 1 H, COCH), 3.67 (dd, J = 3.7, 12.4 Hz, 1 H, CH CHCH OH), 3.94 (dd, J = 2.7,
2 2
13
2.4 Hz, 1 H, CH CHCH OH), 4.60-4.64 (m, 1 H, CH CHCH OH) ppm; C NMR (126 MHz,
2
2
2
2
CDCl ): δ = 12.5 (q, J = 2.9 Hz, CH ), 26.5 (CH CHCH OH), 38.7 (q, J = 26.6 Hz,
3
CF
3
2
2
CF
CHCH ), 40.8 (br. m , COCH), 64.3 (CH CHCH OH), 78.2 (CH CHCH OH), 127.3
3
c
2
2
2
2
19
(
q, JCF = 281 Hz, CF ), 176.8 (OCCH) ppm; F NMR (376 MHz, CDCl ): δ = -68.6
3 3
(
d, J = 8.7 Hz, 3 F, CF ) ppm; IR (Film): = 631, 701, 966, 1020, 1062, 1139, 1171, 1199,
3
-1
+
1
264, 1359, 1466, 1768, 2953, 2989, 3427 cm ; HRMS (ESI): m/z [M+Na] calcd. for
+
[
C H F NaO ] : 235.0553; found: 235.0554.
8
11
3
3
22
1
(
8b) [α]D = -22.9 (c = 1.00, CHCl ); H NMR (500 MHz, CDCl ): δ = 1.39 (d, J = 6.7 Hz, 3 H,
3 3
CH ), 2.03 (br. m, 1 H, OH), 2.11-2.18 (m, 1 H, CH CHCH OH), 2.35-2.40 (m, 1 H,
3
2
2
CH CHCH OH) 2.68-2.76 (m, 2 H, CHCH , COCH), 3.66 (dd, J = 4.8, 12.7 Hz, 1 H,
2
2
3
CH CHCH OH), 3.94 (dd, J = 2.8, 12.7 Hz, 1 H, CH CHCH OH), 4.46-4.51 (m, 1 H,
2
2
2
2
13
CH CHCH OH) ppm; C NMR (126 MHz, CDCl ): δ = 12.3 (q, J = 3.1 Hz, CH ), 27.5
2
2
3
CF
3
(
CH CHCH OH), 38.8 (q, JCF = 26.8 Hz, CHCH3), 41.9 (br. mc, COCH), 63.3
2 2
(
CH CHCH OH), 78.5 (CH CHCH OH), 127.2 (q, J = 280 Hz, CF ), 175.4 (OCCH) ppm;
2 2 2 2 CF 3
19
F NMR (376 MHz, CDCl ): δ = -69.1 (d, J = 8.0 Hz, 3 F, CF ) ppm; IR (Film): = 744, 913,
3
3
-1
9
70, 1046, 1141, 1170, 1201, 1266, 1353, 1396, 1465, 1768, 2928, 2992, 3420 cm ; HRMS
+
+
(
ESI): m/z [M+Na] calcd. for [C H F NaO ] : 235.0553; found: 235.0569.
8 11 3 3
Synthesis of Fluoroalkylated Hydroxy γ-Butyrolactones
(
(
S)-4-Benzyl-3-[(2S,3R,E)-3-hydroxy-2-(2,2,2-trifluoroethyl)hex-4-enoyl]oxazolidin-2-one
10b)
[3]
Following the typical procedure, a solution of 9a (500 mg, 1.66 mmol), TiCl (191 μL,
4
1.74 mmol), (-)-sparteine (953 μL, 4.15 mmol), and (E)-crotonaldehyde (176 μL, 2.16 mmol)
in CH Cl (11.8 mL) was stirred at 0 °C for 3 h. After work-up, the crude product (dr > 95:5,
2
2
19
F NMR) was purified by flash column chromatography (SiO , ethyl acetate/hexane 1:2) to
2
afford 475 mg (77%, 1.28 mmol) of syn-aldol derivate 10b as colorless oil.
6

22
1
[
α]D = +43.5 (c = 2.00, CHCl ); H NMR (500 MHz, CDCl ): δ = 1.71 (d, J = 7.2 Hz, 3 H,
3 3
CHCH=CHCH ), 2.39-2.49 (m, 1 H, CH CF ), 2.61 (br. s, 1 H, OH), 2.67 (dd, J = 13.4,
3
2
3
1
4
0.0 Hz, 1 H, CH Ph), 2.83 (m , 1 H, CH CF ), 3.31 (dd, J = 13.4, 3.2 Hz, 1 H, CH Ph), 4.14-
2 c 2 3 2
.17 (m, 2 H, OCH ), 4.31 (m , 1 H, CHCH=CHCH ), 4.51 (ddd, J = 10.9, 5.3, 1.7 Hz, 1 H,
2
c
3
COCH), 4.68 (m , 1 H, NCH), 5.51 (m , 1 H, CHCH=CHCH ), 5.77 (m , 1 H, CHCH=CHCH ),
c
c
3
c
3
13
7
.20-7.34 (5 H, Ph) ppm; C NMR (126 MHz, CDCl ): δ = 17.6 (CHCH=CHCH ), 31.7
3 3
(
q, JCF = 29.2 Hz, CH CF ), 37.4 (CH Ph), 42.4 (m , COCH), 55.5 (NCH), 66.1 (OCH ), 73.0
2 3 2 c 2
(
CHCH=CHCH ), 126.7 (q, J = 277 Hz, CH CF ), 127.3 (para-Ar-C), 128.9 (ortho-Ar-C),
3 CF 2 3
1
29.2 (CHCH=CHCH ), 129.3 (meta-Ar-C), 129.8 (CHCH=CHCH ), 135.1 (Ar-C), 153.4
3
3
19
(
OCON), 172.5 (NCOC) ppm; F NMR (376 MHz, CDCl ): δ = -64.7 (t, J = 11.0 Hz, 3 F, CF )
3 3
ppm; IR (Film): = 653, 704, 740, 762, 839, 972, 1030, 1101, 1148, 1260, 1360, 1454, 1481,
-1
+
1
604, 1696, 1769, 2860, 2921, 2968, 3031, 3479 cm ; HRMS (ESI): m/z [M+Na] calcd. for
+
[
C H F NNaO ] : 394.1237; found: 394.1250.
18
20
3
4
(
S)-4-Benzyl-3-[(2S,3R,E)-3-hydroxy-5-phenyl-2-(2,2,2-trifluoroethyl)pent-4-
enoyl]oxazolidin-2-one (10c) and (S)-4-Benzyl-3-[(2R,3S,E)-3-hydroxy-5-phenyl-2-(2,2,2-
trifluoroethyl]pent-4-enoyl)oxazolidin-2-one (10c')
[3]
Following the typical procedure, a solution of 9a (650 mg, 2.16 mmol), TiCl (248 μL,
4
2.27 mmol), (-)-sparteine (1.24 mL, 5.40 mmol), and (E)-cinnamaldehyde (353 μL,
2
.81 mmol) in CH Cl (15.3 mL) was stirred at 0 °C for 2 h. After work-up, the crude product
2
2
19
(
dr = 90:10,
F NMR) was purified by flash column chromatography (SiO , ethyl
2
acetate/hexane 2:7 → 2:5) to afford 603 mg (64%, 1.39 mmol) of syn-aldol derivate 10c as
[4]
colorless, foamy oil and 38.0 mg (4.0%, 0.088 mmol) of syn-aldol 10c' as colorless oil.
22
1
[
α]D = +129 (c = 2.00, CHCl ); H NMR (500 MHz, CDCl ): δ = 2.53-2.63 (m, 1 H, CH CF ),
3 3 2 3
2
.68 (dd, J = 13.5, 10.0 Hz, 1 H, CH Ph), 2.77 (br. s, 1 H, OH), 2.94 (m , 1 H, CH CF ), 3.31
2 c 2 3
(
dd, J = 13.5, 3.2 Hz, 1 H, CH Ph), 3.92 (m , 1 H, OCH ), 4.09 (dd, J = 9.1, 2.6 Hz, 1 H,
2 c 2
7

*
*
OCH ), 4.53 (m , 1 H, CHCH=CHPh), 4.63 (m , 1 H, NCH), 4.68 (m , 1 H, COCH),
2
c
c
c
6
7
3
7
.25 (dd, J = 15.9, 6.9 Hz, 1 H, CHCH=CHPh), 6.64 (d, J = 15.9 Hz, 1 H, CHCH=CHPh),
*
13
.20-7.40 (10 H, Ph, CHCH=CHPh) ppm; signal overlap; C NMR (126 MHz, CDCl ): δ =
3
1.8 (q, JCF = 29.3 Hz, CH CF ), 37.4 (CH Ph), 42.8 (m , COCH), 55.5 (NCH), 66.1 (OCH ),
2
3
2
c
2
3.3 (CHCH=CHPh), 126.7 (q, JCF = 277 Hz, CH CF ), 126.5 (Ar), 127.2 (Ar), 127.3
2
3
(
CHCH=CHPh), 128.3 (Ar), 128.7 (Ar), 128.9 (Ar), 129.3 (Ar), 132.8 (CHCH=CHPh), 135.0
19
(
Ar-C), 135.7 (Ar-C), 153.5 (OCON), 172.4 (NCOC) ppm; F NMR (376 MHz, CDCl ): δ =
3
-
64.6 (t, J = 11.0 Hz, 3 F, CF ) ppm; IR (Film): = 699, 736, 911, 972, 1016, 1100, 1147,
3
-1
1
210, 1261, 1353, 1393, 1453, 1496, 1697, 1779, 2921, 3029, 3485, cm ; HRMS (ESI): m/z
+
+
[
M+Na] calcd. for [C H F NNaO ] : 456.1393; found: 456.1408.
23 22 3 4
22
1
[
α]D = -3.91 (c = 0.61, CHCl ); H NMR (500 MHz, CDCl ): δ = 2.35-2.45 (m, 1 H, CH CF ),
3 3 2 3
2
.55 (dd, J = 13.5, 10.1 Hz, 1 H, CH Ph), 2.73 (d, J = 8.1 Hz 1 H, OH), 2.83-2.96 (m, 1 H,
2
CH CF ), 3.28 (dd, J = 13.6, 3.2 Hz, 1 H, CH Ph), 4.12-4.24 (m, 2 H, OCH ), 4.50-4.55 (m,
2
3
2
2
1°H, CHCH=CHPh), 4.59-4.74 (m, 2 H, NCH, COCH), 6.28 (dd, J = 15.8, 6.0 Hz, 1 H,
CHCH=CHPh), 6.69 (d, J = 15.8 Hz, 1 H, CHCH=CHPh), 7.14-7.40 (10 H, Ph, CHCH=CHPh)
13
ppm; C NMR (101 MHz, CDCl ): δ = 33.6 (q, J = 29.6 Hz, CH CF ), 37.7 (CH Ph), 42.1
3
CF
2
3
2
(
(
m , COCH), 55.8 (NCH), 66.2 (OCH ), 74.1 (CHCH=CHPh), 126.7 (Ar), 127.4 (Ar), 127.9
c 2
CHCH=CHPh), 128.3 (Ar), 128.8 (Ar), 129.0 (Ar), 129.3 (Ar), 133.1 (CHCH=CHPh), 135.1
(
Ar-C), 135.7 (Ar-C), 153.6 (OCON), 172.0 (NCOC) ppm; signal for CF was not found;
3
19
F NMR (376 MHz, CDCl ): δ = -64.9 (t, J = 10.5 Hz, 3 F, CF ) ppm; IR (Film): = 697, 749,
3
3
-1
9
72, 1017, 1103, 1147, 1211, 1260, 1352, 1392, 1495, 1699, 1780, 2923, 3029, 3485 cm ;
+
+
HRMS (ESI): m/z [M+Na] calcd. for [C H F NNaO ] : 456.1393; found: 456.1379.
23
22
3
4
(
S)-4-Benzyl-3-{(S)-4,4,5,5,6,6,6-heptafluoro-2-[(R)-1-hydroxyallyl]hexanoyl}oxazolidin-
-one (10d)
2
[
1]
Following the typical procedure, a solution of 9b (105 mg, 0.262 mmol), TiCl (30.2 μL,
4
0.275 mmol), (-)-sparteine (150 μL, 0.654 mmol), and acroleine (22.7 μL, 0.340 mmol) in
CH Cl (2.2 mL) was stirred at 0 °C for 2 h. After work-up, the crude product (dr > 95:5,
2
2
19
F NMR) was purified by flash column chromatography (SiO , ethyl acetate/hexane 1:2) to
2
afford 86.0 mg (71%, 0.188 mmol) of syn-aldol derivate 10d as light yellow oil.
8

22
1
[
α]D = +31.1 (c = 1.00, CHCl ); H NMR (500 MHz, CDCl ): δ = 2.27 (d, J ~ 3.4 Hz, 1 H,
3 3
OH), 2.33-2.44 (m, 1 H, CH C F ), 2.26 (dd, J = 13.4, 10.2 Hz, 1 H, CH Ph), 2.84-2.97 (m,
2
3
7
2
1
1
5
H, CH C F ), 3.35 (dd, J = 13.4, 3.4 Hz, 1 H, CH Ph), 4.19-4.20 (m, 2 H, OCH ), 4.46 (m ,
2 3 7 2 2 c
°H, CHCH=CH ), 4.63 (ddd, J = 10.8, 4.5, 1.8 Hz, 1 H, COCH), 4.68-4.73 (m, 1 H, NCH),
2
.30-5.41 (m, 2 H, CHCH=CH ), 5.88 (m , 1 H, CHCH=CH ), 7.22-7.35 (5 H, Ph) ppm;
2
c
2
13
C NMR (126 MHz, CDCl ): δ = 28.0 (q, J = 21.1 Hz, CH C F ), 37.4 (CH Ph), 40.6 (m ,
3
CF
2
3
7
2
c
COCH), 55.6 (NCH), 66.2 (OCH ), 73.0 (CHCH=CH ), 117.9 (CHCH=CH ), 127.4 (para-Ar-
2
2
2
C), 129.0 (ortho-Ar-C), 129.4 (meta-Ar-C), 135.1 (Ar-C), 136.2 (CHCH=CH ), 153.4 (OCON),
2
1
72.5 (NCOC) ppm; signals for CF CF CF , CF CF CF , CF CF CF could not be detected;
2 2 3 2 2 3 2 2 3
19
F NMR (376 MHz, CDCl ): δ = -80.3 (t, J = 9.9 Hz, 3 F, CF CF CF ), -113.2 (m , 2 F,
3
2
2
3
c
CF CF CF ), -127.5 (m , 2 F, CF CF CF ) ppm; IR (Film): = 702, 723, 935, 970, 1014,
2
2
3
c
2
2
3
-1
+
1
101, 1224, 1291, 1354, 1394, 1703, 1781, 2924, 3478 cm ; HRMS (ESI): m/z [M+Na]
+
calcd. for [C H F NNaO ] : 480.1016; found: 480.1043.
19
18
7
4
(
S)-4-Benzyl-3-{(2S,3R)-3-hydroxy-2-[(R)-1,1,1-trifluorobutan-2-yl]pent-4-
enoyl}oxazolidin-2-one (10e)
[
1]
Acyl-oxazolidinone 3 (390 mg, 1.18 mmol) was dissolved in dichloromethane (12.0 mL) and
TiCl (138 μL, 1.25 mmol) was added dropwise at -78 °C. The solution was warmed to 0 °C
4
and stirred for 10 min before N,N-diisopropylethylamine (0.489 mL, 2.96 mmol) was added
dropwise. The resulting dark brown solution was stirred at 0 °C for 1 h. The mixture was
cooled to -78 °C, and freshly distilled acroleine (119 μL, 1.78 mmol) was added. After 1 h, the
solution was warmed to 0 °C and stirred at that temperature for 12 h. The reaction was then
allowed to warm to rt and aqueous saturated ammonium chloride solution (3.5 mL) was
added. The mixture was filtered over celite and the aqueous phase was extracted with
dichloromethane (4 x 5.0 mL). The combined organic phases were washed with aqueous
saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and
19
concentrated in vacuo. The crude product (dr = 76:24, F NMR) was purified flash column
chromatography (SiO , ethyl acetate/hexane 1:4 → 1:3) to afford 170 mg (37%, 0.441 mmol)
2
of syn-aldol derivative 10e as light yellow oil and 65.0 mg (14%, 0.169 mmol) of a mixture of
the minor diastereoisomers as light yellow oil.
9

22
1
[
α]D = +12.2 (c = 1.00, CHCl ); H NMR (500 MHz, CDCl ): δ = 1.06 (t, J = 7.7 Hz, 3 H,
3 3
CH CH ), 1.66-1.74 (m, 1 H, CH CH ), 1.76-1.84 (m, 1 H, CH CH ), 2.57 (dd, J = 13.4,
2
3
2
3
2
3
1
3
1
0.0 Hz, 1 H, CH Ph), 2.70 (br. s, 1 H, OH), 2.76-2.86 (m, 1 H, CHCF ), 3.34 (dd, J = 13.4,
2 3
.4 Hz, 1 H, CH Ph), 4.10-4.16 (m, 2 H, OCH ), 4.56 (m , 1 H, CHCH=CH ), 4.68-4.74 (m,
2
2
c
2
H, NCH), 4.78 (dd, J = 10.0, 5.8 Hz, 1 H, COCH), 5.30-5.38 (m, 2 H, CHCH=CH ), 6.06
2
13
(
ddd, J = 17.4, 10.5, 7.2 Hz, 1 H, CHCH=CH ), 7.20-7.34 (5 H, Ph) ppm; C NMR (126 MHz,
2
CDCl ): δ = 10.9 (CH CH ), 18.6 (m , CH CH ), 37.4 (CH Ph), 43.5 (q, J = 24.4 Hz,
3
2
3
c
2
3
2
CF
CHCF ), 44.7 (m , COCH), 55.0 (NCH), 66.0 (OCH ), 72.0 (CHCH=CH ), 118.5
3
c
2
2
(
CHCH=CH ), 126.7 (q, J = 278 Hz, CF ), 127.2 (para-Ar-C), 128.9 (ortho-Ar-C), 129.3
2 CF 3
19
(
meta-Ar-C), 135.4 (Ar-C), 135.8 (CHCH=CH ), 153.9 (OCON), 172.0 (NCOC) ppm; F NMR
2
(
376 MHz, CDCl ): δ = -65.3 (d, J = 8.6 Hz, 3 F, CF ) ppm; IR (Film): = 702, 741, 913,
3
3
-1
1
011, 1052, 1107, 1171, 1211, 1247, 1352, 1389, 1699, 1781, 2976, 3485 cm ; HRMS
+
+
(
ESI): m/z [M+Na] calcd. for [C H F NNaO ] : 408.1393; found: 408.1383.
19 22 3 4
(
S)-4-Benzyl-3-{(2S,3R)-3-[(tert-butyldimethylsilyl)oxy]-2-[(R)-1,1,1-trifluorobutan-2-
yl]pent-4-enoyl}oxazolidin-2-one (10f)
TBSOTf (50.8 μL, 0.221 mmol) was added dropwise to a solution of syn-aldol derivative 10e
(50.0 mg, 0.130 mmol) and 2,6-lutidine (45.2 μL, 0.390 mmol) in dichloromethane (0.5 mL) at
0
°C. The reaction mixture was stirred at 0 °C for 6 h and was then allowed to warm to rt
overnight. The reaction was quenched by the addition of aqueous saturated ammonium
chloride solution (1.5 mL). The aqueous layer was extracted with diethylether (4 x 2 mL). The
combined organic phases were washed with cold aqueous 0.1 N HCl solution and with
aqueous saturated NaHCO solution, dried over sodium sulfate, filtered, and concentrated in
3
vacuo. The crude product was purified by flash column chromatography (SiO , ethyl
2
acetate/hexane 1:9) to afford 49.0 mg (75%, 0.098 mmol) of 10f as colorless oil.
22
1
[
α]D = +22.8 (c = 1.00, CHCl ); H NMR (500 MHz, CDCl ): δ = 0.04 (s, 3 H, Si(CH ) ), 0.07
3 3 3 2
(
s, 3 H, Si(CH ) ), 0.84 (s, 9 H, SiC(CH ) ), 1.07 (t, J = 7.5 Hz, 3 H, CH CH ), 1.65-1.81 (m,
3 2 3 3 2 3
1
0

2
H, CH CH ), 2.57 (dd, J = 13.4, 10.8 Hz, 1 H, CH Ph), 2.66-2.76 (m, 1 H, CHCF ), 3.40
2 3 2 3
(
dd, J = 13.4, 3.4 Hz, 1 H, CH Ph), 4.03-4.07 (m, 1 H, OCH ), 4.10-4.14 (m, 1 H, OCH ), 4.47
2 2 2
(
m , 1°H, CHCH=CH ), 4.68 (m , 1 H, NCH), 4.85 (dd, J = 10.0, 6.4 Hz, 1 H, COCH), 5.20-
c 2 c
5
.29 (m, 2 H, CHCH=CH ), 6.06 (ddd, J = 17.4, 10.4, 8.0 Hz, 1 H, CHCH=CH ), 7.24-7.34
2
2
13
(
5 H, Ph) ppm; C NMR (126 MHz, CDCl ): δ = -5.10 (Si(CH ) ), -4.56 (Si(CH ) ), 10.8
3 3 2 3 2
(
CH CH ), 17.9 (m , CH CH ), 18.7 (SiC(CH ) ), 25.6 (SiC(CH ) ), 37.4 (CH Ph), 43.5
2 3 c 2 3 3 3 3 3 2
(
q, JCF = 24.5 Hz, CHCF ), 44.9 (m , COCH), 55.7 (NCH), 65.5 (OCH ), 73.7 (CHCH=CH ),
3 c 2 2
117.7 (CHCH=CH ), 127.2 (para-Ar-C), 127.9 (q, J = 282 Hz, CF ) 128.9 (ortho-Ar-C),
2 CF 3
1
29.4 (meta-Ar-C), 135.7 (Ar-C), 137.2 (CHCH=CH ), 153.0 (OCON), 171.8 (NCOC) ppm;
2
19
F NMR (376 MHz, CDCl ): δ = -65.1 (d, J = 8.8 Hz, 3 F, CF ) ppm; IR (Film): = 682, 701,
3
3
-1
7
79, 838, 867, 1073, 1102, 1173, 1251, 1350, 1382, 1402, 1703, 1788, 2858, 2955 cm ;
+
+
HRMS (ESI): m/z [M+Na] calcd. for [C H F NNaO Si] : 522.2258; found: 522.2288.
25
36
3
4
(
S)-4-Benzyl-3-{(2S,3R)-3-[(tert-butyldimethylsilyl)oxy]-2-(2,2,2-trifluoroethyl)pent-4-
enoyl}oxazolidin-2-one (10g)
TBSOTf (317 μL, 1.38 mmol) was added dropwise to a solution of syn-aldol derivative 10a
(290 mg, 0.812 mmol) and 2,6-lutidine (282 μL, 2.44 mmol) in dichloromethane (2.9 mL) at
0
°C. The reaction mixture was stirred at 0 °C for 5 h and was then allowed to warm to rt
overnight. The reaction was quenched by the addition of aqueous saturated ammonium
chloride solution (3.5 mL). The aqueous layer was extracted with dichloromethane (4 x 4
mL). The combined organic phases were washed with cold aqueous 0.1 N HCl solution and
with aqueous saturated NaHCO3 solution, dried over sodium sulfate, filtered, and
concentrated in vacuo. The crude product was purified by flash column chromatography
(
SiO , ethyl acetate/hexane 1:11) to afford 322 mg (84%, 0.683 mmol) of 10g as light yellow
2
oil.
22
1
[
α]D = +50.9 (c = 2.00, CHCl ); H NMR (500 MHz, CDCl ): δ = 0.00 (s, 6 H, Si(CH ) ), 0.90
3 3 3 2
(
s, 9 H, SiC(CH ) ), 2.34-2.44 (m, 1 H, CH CF ), 2.75 (dd, J = 13.5, 9.7 Hz, 1 H, CH Ph),
3 3 2 3 2
2.89 (m , 1 H, CH CF ), 3.28 (dd, J = 13.5, 3.1 Hz, 1 H, CH Ph), 4.12-4.20 (m, 2 H, OCH ),
c 2 3 2 2
4
.36-4.41 (m, 2 H, COCH, CHCH=CH ), 4.64 (m , 1 H, NCH), 5.21-5.29 (m, 2 H,
2
c
CHCH=CH ), 5.88 (ddd, J = 17.0, 10.4, 5.5 Hz, 1 H, CHCH=CH ), 7.21-7.35 (5 H, Ph) ppm;
2
2
1
1

13
C NMR (126 MHz, CDCl ): δ = -5.40 (Si(CH ) ), -4.60 (Si(CH ) ), 18.0 (SiC(CH ) ), 25.6
3
3 2
3 2
3 3
(
SiC(CH ) ), 30.6 (q, J = 29.1 Hz, CH CF ), 37.3 (CH Ph), 43.3 (m , COCH), 55.6 (NCH),
3 3 CF 2 3 2 c
6
1
1
3
1
5.9 (OCH ), 73.9 (CHCH=CH ), 116.8 (CHCH=CH ), 126.9 (q, J = 277 Hz, CH CF ),
2 2 2 CF 2 3
27.3 (para-Ar-C), 128.9 (ortho-Ar-C), 129.4 (meta-Ar-C), 135.1 (Ar-C), 137.9 (CHCH=CH2),
19
53.1 (OCON), 171.4 (NCOC) ppm; F NMR (376 MHz, CDCl ): δ = -64.8 (t, J = 11.1 Hz,
3
F, CF ) ppm; IR (Film): = 649, 703, 739, 779, 836, 939, 1031, 1102, 1135, 1211, 1264,
3
-1
+
362, 1391, 1472, 1705, 1790, 2859, 2931, 2956, 2956 cm ; HRMS (ESI): m/z [M+Na]
+
calcd. for [C H F NNaO Si] : 494.1945; found: 494.1964.
23
32
3
4
(
3S,4S,5R)-4-Hydroxy-5-[(S)-1-hydroxyethyl]-3-(2,2,2-trifluoroethyl)dihydrofuran-2(3H)-
one (11b)
Following the typical procedure, a solution of 10b (183 mg, 0.492 mmol, dissolved in 1.4 mL
acetone/water 8:1), K OsO ·2H O (18.1 mg, 49.2 μmol, 10 mol%), and N-methylmorpholine-
2
4
2
N-oxide (115 mg, 0.984 mmol) in acetone/water 8:1 (1.0 mL) was stirred for 17 h. After work-
19
up, the crude product (dr = 93:7, F NMR) was purified by flash column chromatography
SiO , dichloromethane/methanol 30:1.7) to afford 60.0 mg (53%, 0.263 mmol) of 11b as a
(
2
colorless solid.
22
1
mp 102-105 °C; [α]D = +31.7 (c = 1.00, MeOH); H NMR (500 MHz, MeOD): δ = 1.30 (d,
H, J = 6.6 Hz, CHCHOHCH ), 2.48-2.59 (m, 1 H, CH CF ), 2.71 (m , 1 H, CH CF ), 2.90
3
3
2
3
c
2
3
(
m , 1 H, COCH), 3.91 (qd, J = 6.6, 3.2 Hz, 1 H, CHCHOHCH ), 4.05 (dd, J = 6.3, 3.2 Hz,
c 3
13
1
H, CHCHOHCH ), 4.27 (m , 1 H, CHCHOH) ppm; signal for OH was not found; C NMR
3 c
(
126 MHz, MeOD): δ = 19.8 (CHCHOHCH ), 33.8 (q, J = 30.3 Hz, CH CF ), 45.1 (q, J
=
=
3
CF
2
3
CF
CF
2
.4 Hz, COCH), 67.0 (CHCHOHCH ), 73.9 (CHCHOH), 89.6 (CHCHOHCH ), 127.9 (q, J
3 3
19
2
76 Hz, CF ), 176.5 (OCOC) ppm; F NMR (376 MHz, MeOD): δ = -65.8 (t, J = 11.0 Hz,
3
CF ) ppm; IR (Film): = 622, 837, 993, 1054, 1083, 1146, 1234, 1264, 1368, 1439, 1770,
3
-1
+
+
2
937, 2983, 3401 cm . HRMS (ESI): m/z [M+Na] calcd. for [C H F NaO ] : 251.0502;
8 11 3 4
found: 251.0516.
(
3S,4S,5S)-4-Hydroxy-5-[(S)-hydroxy(phenyl)methyl]-3-(2,2,2-trifluoroethyl)-
dihydrofuran-2(3H)-one (11c)
1
2

Following the typical procedure, a solution of 10c (263 mg, 0.607 mmol, dissolved in 1.7 mL
acetone/water 8:1), K OsO ·2H O (22.4 mg, 60.7 μmol, 10 mol%), and N-methylmorpholine-
2
4
2
N-oxide (142 mg, 1.22 mmol) in acetone/water 8:1 (1.2 mL) was stirred for 17 h. After work-
19
up, the crude product (dr > 95:5, F NMR) was purified by flash column chromatography
SiO , dichloromethane/methanol 30:0.8) to afford 84.0 mg (47%, 0.289 mmol) of 11c as a
(
2
colorless solid.
22
1
mp 67-70 °C; [α]D = +45.2 (c = 0.60, MeOH); H NMR (500 MHz, MeOD): δ = 2.37-2.48 (m,
H, CH CF ), 2.66 (m , 1 H, CH CF ), 2.88 (ddd, J = 9.6, 6.9, 3.8 Hz, 1 H, COCH), 4.38 (dd,
1
2
3
c
2
3
J = 5.6, 2.5 Hz,1 H, CHCHOHPh), 4.43-4.46 (m, 1 H, CHCHOH), 4.89 (d, J = 6.2 Hz, 1 H,
CHCHOHPh), 7.27-7.30 (m, 1 H, Ph), 7.34-7.38 (m, 2 H, Ph), 7.40-7.44 (m, 2 H, Ph) ppm;
13
signal for OH was not found; C NMR (126 MHz, MeOD): δ = 33.8 (q, JCF = 30.2 Hz,
CH CF ), 45.2 (q, J = 2.5 Hz, COCH), 72.7 (CHCHOHPh), 73.8 (CHCHOH), 89.8
2
3
CF
(
CHCHOHPh), 127.8 (ortho-Ar-C), 127.9 (q, JCF = 276 Hz, CF ), 128.8 (para-Ar-C), 129.3
3
19
(
meta-Ar-C), 142.2 (Ar-C), 176.7 (OCOC) ppm; F NMR (376 MHz, MeOD): δ = -64.0
(
t, J = 10.7 Hz, CF ) ppm; IR (Film): = 623, 648, 702, 741, 843, 913, 950, 1022, 1148,
3
-1
+
1
230, 1264, 1439, 1454, 1776, 2926, 3424 cm . HRMS (ESI): m/z [M+Na] calcd. for
+
[
C H F NaO ] : 313.0658; found: 313.0664.
13
13
3
4
(
3S,4S,5R)-3-(2,2,3,3,4,4,4-Heptafluorobutyl)-4-hydroxy-5-(hydroxymethyl)-
dihydrofuran-2(3H)-one (11d)
Following the typical procedure, a solution of 10d (50 mg, 0.109 mmol, dissolved in 0.5 mL
acetone/water 8:1), K OsO ·2H O (4.00 mg, 10.9 μmol, 10 mol%), and N-methylmorpholine-
2
4
2
N-oxide (25.6 mg, 0.219 mmol) in acetone/water 8:1 (0.8 mL) was stirred for 17 h. After
19
work-up, the crude product (dr = 91:9,
F NMR) was purified by flash column
chromatography (SiO , dichloromethane/methanol 20:1) to afford 16.5 mg (48%, 52.5 μmol)
2
of 11d as a colorless solid.
1
3

22
1
mp 95-98 °C; [α]D = +17.8 (c = 0.50, C H O); H NMR (500 MHz, C D O): δ = 2.56-2.75 (m,
3
6
3
6
2
H, CH C F ), 3.07 (m , 1 H, COCH), 3.72-3.76 (m, 1 H, CHCH OH), 3.89-3.94 (m, 1 H,
2 3 7 c 2
CHCH OH), 4.28 (m , 1 H, CHCH OH), 4.32 (m , 1 H, CHCH OH), 4.40-4.44 (m, 1 H,
2
c
2
c
2
13
CHCHOH), 5.04 (d, J = 5.9, 1 H, CHCHOH) ppm; C NMR (126 MHz, C D O): δ = ~29.8
3
6
(
m , CH C F ), 43.4 (m , COCH), 61.2 (CHCH OH), 73.2 (CHCHOH), 86.3 (CHCH OH),
c 2 3 7 c 2 2
1
75.2 (OCOC) ppm; signals for CF CF CF , CF CF CF , CF CF CF could not be detected;
2 2 3 2 2 3 2 2 3
19
F NMR (376 MHz, C D O): δ = -81.3 (t, J = 9.9 Hz, 3 F, CF CF CF ), -113.7 (m , 2 F,
3
6
2
2
3
c
CF CF CF ), -128.4 (m , 2 F, CF CF CF ) ppm; IR (Film): = 666, 731, 993, 1046, 1114,
2
2
3
c
2
2
3
-1
+
1
176, 1224, 1307, 1337, 1361, 1756, 2326 cm ; HRMS (ESI): m/z [M+Na] calcd. for
+
[
C H F NaO ] : 337.0281; found: 337.0288.
9
9
7
4
(
3S,4S,5R)-4-[(tert-Butyldimethylsilyl)oxy]-5-(hydroxymethyl)-3-[(R)-1,1,1-trifluoro-
butan-2-yl]dihydrofuran-2(3H)-one (11f)
Following the typical procedure, a solution of 10f (126 mg, 0.252 mmol, dissolved in 1.3 mL
acetone/water 8:1), K OsO ·2H O (9.28 mg, 25.2 μmol, 10 mol%), and N-methylmorpholine-
2
4
2
N-oxide (59.0 mg, 0.504 mmol) in acetone/water 8:1 (1.2 mL) was stirred for 16 h. After
19
work-up, the crude product (dr = 93:7,
F-NMR) was purified by flash column
chromatography (SiO , ethylacetate/hexane 1:3) to afford 37.8 mg (42%, 0.106 mmol) of 11f
2
as a colorless oil.
22
1
[
α]D = +2.40 (c = 1.00, CHCl ); H NMR (500 MHz, CDCl ): δ = 0.10 (s, 6 H, Si(CH ) ), 0.87
3 3 3 2
(
s, 9 H, SiC(CH ) ), 1.01 (t, J = 7.5, 3 H, CH CH ), 1.53 (m , 1 H, CH CH ), 1.76-1.87 (m,
3 3 2 3 c 2 3
1
1
H, CH CH ), 2.11 (br. s, 1 H, OH), 2.68-2.77 (m, 1 H, CHCF ), 3.11 (dd, J = 7.8, 2.4 Hz,
2 3 3
H, COCH), 3.77 (dd, J = 12.9, 3.1 Hz, 1 H, CHCH OH), 4.02 (dd, J = 12.9, 2.3 Hz, 1 H,
2
13
CHCH OH), 4.21 (m , 1 H, CHCH OH), 4.66 (m , 1 H, CHCHOTBS) ppm; C NMR (126
2
c
2
c
MHz, CDCl ): δ = -5.03 (Si(CH ) ), -3.97 (Si(CH ) ), 12.3 (CH CH ), 17.8 (SiC(CH ) ), 19.0
3
3 2
3 2
2
3
3 3
1
4

(
(
(
(
m , CH CH ), 25.6 (SiC(CH ) ), 43.4 (q, J = 26.4 Hz, CHCF ), 49.2 (m , COCH), 60.6
c 2 3 3 3 CF 3 c
CHCH OH), 68.6 (CHCHOTBS), 85.2 (CHCH OH), 127.4 (q, J = 280 Hz, CF ), 174.2
2
2
CF
3
19
OCOC) ppm; F NMR (376 MHz, CDCl ): δ = -66.9 (d, J = 10.3 Hz, 3 F, CF ) ppm; IR
3
3
-1
Film): = 779, 839, 1040, 1146, 1177, 1258, 1390, 1465, 1777, 2860, 2933, 2953 cm .
+
+
HRMS (ESI): m/z [M+Na] calcd. for [C H F NaO Si] : 379.1523; found: 379.1515.
15
27
3
4
(
3S,4S,5R)-4-[(tert-Butyldimethylsilyl)oxy]-5-(hydroxymethyl)-3-(2,2,2-
trifluoroethyl)dihydrofuran-2(3H)-one (11g)
Following the typical procedure, a solution of 10g (164 mg, 0.348 mmol, dissolved in 1.0 mL
acetone/water 8:1), K OsO ·2H O (12.8 mg, 34.8 μmol, 10 mol%), and N-methylmorpholine-
2
4
2
N-oxide (81.5 mg, 0.696 mmol) in acetone/water 8:1 (0.8 mL) was stirred for 15 h. After
19
work-up, the crude product (dr = 95:5,
F NMR) was purified by flash column
chromatography (SiO , ethyl acetate/hexane 1:6 → 1:4) to afford 63.0 mg (55%, 0.192 mmol)
2
of 11g as a colorless solid.
22
1
mp 53-56 °C; [α]D = +3.08 (c = 0.12, CHCl ); H NMR (500 MHz, CDCl ): δ = 0.09 (s, 6 H,
3
3
Si(CH ) ), 0.88 (s, 9 H, SiC(CH ) ), 2.49-2.67 (m, 3 H, CH CF , CHCH OH), 2.86-2.90 (m,
3
2
3 3
2
3
2
1
H, COCH), 3.71 (dd, J = 12.8, 2.4 Hz,1 H, CHCH OH), 3.99 (dd, J = 12.8, 2.2 Hz, 1 H,
2
13
CHCH OH), 4.29 (m , 1 H, CHCH OH), 4.46 (m , 1 H, CHCHOTBS) ppm; C NMR (126
2
c
2
c
MHz, CDCl ): δ = -4.96 (Si(CH ) ), -4.56 (Si(CH ) ), 17.7 (SiC(CH ) ), 25.5 (SiC(CH ) ), 32.4
3
3 2
3 2
3 3
3 3
(
q, JCF = 30.2 Hz, CH CF ), 45.3 (q, J = 2.5 Hz, COCH), 60.6 (CHCH OH), 72.9
2 3 CF 2
19
(
CHCHOTBS), 86.5 (CHCH OH), 126.1 (q, J = 277 Hz, CF ), 175.6 (OCOC) ppm; F-NMR
2 CF 3
(
376 MHz, CDCl ): δ = -64.2 (t, J = 10.9 Hz, CF ) ppm; IR (Film): = 608, 782, 838, 898,
3 3
-1
1
008, 1081, 1150, 1227, 1263, 1378, 1766, 2860, 2932, 2958, 3294 cm . HRMS (ESI): m/z
+
+
[
M+Na] calcd. for [C H F NaO Si] : 351.1210; found: 351.1220.
13 23 3 4
(
(
3S,4S,5R)-4-Hydroxy-5-(hydroxymethyl)-3-(2,2,2-trifluoroethyl)dihydrofuran-2(3H)-one
11a) from (11g)
Protected syn-aldol derivative 11g (40.0 mg, 0.122 mmol) was dissolved in dichloromethane
1.1 ml) and treated with triethylamine trishydrofluoride (37% in Et N, 134 μL, 0.305 mmol) at
(
3
1
5

rt for 17 h. The mixture was diluted with dichloromethane (10 mL) and brine (6 mL) was
added. The aqueous layer was extracted with ethyl acetate (3 x 6 mL). The combined
organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The
crude
product
was
purified
by
flash
column
chromatography
(SiO2,
dichloromethane/methanol 20:1) to afford 21.0 mg (80%, 98.0 μmmol) of 11a as a colorless
solid.
1
6

Compound 7
1
H NMR (500 MHz, CDCl3)
13
C NMR (126 MHz, CDCl3)
1
7

19
F NMR (376 MHz, CDCl3)
Compound 4
1
H NMR (500 MHz, CDCl3)
1
8

13
C NMR (126 MHz, CDCl3)
19
F NMR (376 MHz, CDCl3)
1
9

Compound 5
1
H NMR (500 MHz, CDCl3)
13
C NMR (126 MHz, CDCl3)
2
0

19
F NMR (376 MHz, CDCl3)
Compound 8a
1
H NMR (500 MHz, CDCl3)
2
1

13
C NMR (126 MHz, CDCl3)
19
F NMR (376 MHz, CDCl3)
2
2

Compound 8b
1
H NMR (500 MHz, CDCl3)
13
C NMR (126 MHz, CDCl3)
2
3

19
F NMR (376 MHz, CDCl3)
Compound 10a
1
H NMR (500 MHz, CDCl3)
2
4

13
C NMR (126 MHz, CDCl3)
19
F NMR (376 MHz, CDCl3)
2
5

Compound 10b
1
H NMR (500 MHz, CDCl3)
13
C NMR (126 MHz, CDCl3)
2
6

19
F NMR (376 MHz, CDCl3)
Compound 10c
1
H NMR (500 MHz, CDCl3)
2
7

13
C NMR (126 MHz, CDCl3)
19
F NMR (376 MHz, CDCl3)
2
8

Compound 10c’
O
O
OH
O
N
Ph
CF3
Bn
1
H NMR (500 MHz, CDCl3)
13
C NMR (101 MHz, CDCl3)
2
9