Synthesis of both enantiomers of ω-trifluorononactic acid, a new analogue of nonactin monomers

Article abstract of DOI:10.1055/s-0030-1260234

Both (+)- and (-)-ω-trifluorononactic acid, a designed analogue of nonactic acid, were synthesized. The racemic acid, prepared by using cis-selective iodoetherification, was resolved as the corresponding (S)-O-acetylmandelates. The structure was determined by X-ray crystallographic analysis.

Full text of DOI:10.1055/s-0030-1260234

PAPER
3741
Synthesis of Both Enantiomers of w-Trifluorononactic Acid, a New Analogue
of Nonactin Monomers
Kentaro Takai,a Tadaatsu Hanadate,a Shuichi Oi,b Teiko Yamada,a Shigefumi Kuwahara,a Hiromasa Kiyota*a
a
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Sciences, Tohoku University,
1-1 Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
Fax +81(22)7178785; E-mail: kiyota@biochem.tohoku.ac.jp
Environment Conservation Research Institute, Tohoku University, Japan
b
Received 12 July 2011; revised 19 August 2011
R2
O
Abstract: Both (+)- and (–)-w-trifluorononactic acid, a designed
analogue of nonactic acid, were synthesized. The racemic acid, pre-
pared by using cis-selective iodoetherification, was resolved as the
corresponding (S)-O-acetylmandelates. The structure was deter-
mined by X-ray crystallographic analysis.
O
O
O
O
(+)
R3
O
(–)
O
O
O
R1
(–)
O
(+)
O
Key words: polynactins, antibiotics, w-trifluorononactic acid,
chiral resolution, total synthesis
O
R4
polynactins 1
R1
R2
R3
R4
The polynactins, which include 1a–c (Figure 1), are a se-
ries of macrotetrolide antibiotics isolated from Streptomy-
ces strains.1 Their unique structural and biological2
features have led many chemists to synthesize the natural
congeners 1a and 1b,3 and we have reported the total syn-
thesis of a designed polynactin analogue, macrotetrolide a
(1d), composed of (+)- and (–)-bishomononactic acid
(2c).4 Although 1d failed to exhibit either significant im-
munosuppressive or cytotoxic activity, bioactive ana-
logues are still pursued. The isobutyl analogue 1e has also
been reported,5 but no biological studies were undertaken.
As part of our ongoing studies on the chemistry of
polynactins,4,6 we were interested in the synthesis of non-
actic acid analogues bearing a bulky substituent at the 9-
position, such as w-trifluorononactic acid (2d). A trifluo-
romethyl group has been found to be as large as an isopro-
pyl or tert-butyl group, and makes the parent molecule
more hydrophobic.7 We hypothesized this curious nature
of a trifluoromethyl group could confer interesting prop-
erties on the corresponding polynactin, macrotetrolide b
(1f). Here, we describe the synthesis of both enantiomers
of the monomer 2d.
(1a)
nonactin
tetranactin
macrotetrolide B
macrotetrolide α
Me
Et
Et
i-Pr
i-Bu
Me
Et
i-Pr
i-Pr
i-Bu
Me
Et
Et
i-Pr
i-Bu
Me
Et
i-Pr
i-Pr
i-Bu
(1b)
(1c)
(1d)
1e
(1f)
CF3
CF3
CF3
CF3
macrotetrolide β
O
OH
HO
R
O
R
(+)-nonactic acid
(+)-homononactic acid
(+)-bishomononactic acid
[(+)-2a]
[(+)-2b]
[(+)-2c]
Me
Et
i-Pr
(–)-ω-trifluorononactic acid
CF3
[(–)-2d]
Figure 1 Polynactin congeners and their monomers
gative effect of the trifluoromethyl group. Instead, 4 was
prepared from the corresponding alcohol (EZ)-5 by Wittig
reaction11 and oxidation. Iodoetherification12 of 4, howev-
er, did not proceed, perhaps due to the strongly electron-
deficient nature of the double bond. Fortunately, iodo-
A similar procedure to the synthesis of (+)- and (–)-bis- etherification of (EZ)-5 afforded cis-tetrahydrofuran com-
homononactic acid (2c)4 was followed, that is, using cis- pound 7. Only (Z)-5 reacted under these conditions; (E)-5
selective iodoetherification and optical resolution as the was completely recovered. Reductive deiodination of 7
key steps.
gave a separable mixture of 8 and 8-epi-8 in a ratio of 1:1.
The relative configuration of the cis-tetrahydrofuran ring
of 8 was determined by observation of an NOE correlation
between 3-H and 6-H, but we could not elucidate the ste-
reochemistry of the 8-position at this stage.
Initially, enone 4 was sought as a precursor for the iodo-
etherification (Scheme 1). Chain elongation of 34 by the
Horner reaction [(MeO)2P(O)CH2C(O)CF3],8 its enam-
ine-type variation [(EtO)2P(O)CH=C(NH2)CF3],9 and the
Knoevenagel reaction [EtOC(O)CH2C(O)CF3]10 all failed Although 8 was prepared, the overall yield was poor
to give the desired 4, probably due to the strong electrone- (4.3% from 3) and improvements to the route were sought.
Next, we tried a simpler Wittig reaction (Scheme 2). Iodo-
etherification of Z-olefin 9 (prepared by Wittig reaction13)
gave exclusively cis-tetrahydrofuran compound 10,
which was successfully dehydroiodinated to the E-olefin
11, hydroboration of which14 failed, probably due to steric
SYNTHESIS 2011, No. 22, pp 3741–3748
Advanced online publication: 21.09.2011
DOI: 10.1055/s-0030-1260234; Art ID: F69411SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1

3742
K. Takai et al.
PAPER
hindrance. Methylenation of 3 and iodoetherification of
the resulting 12 afforded iodide 13, however, introduction
of a trifluoroacetyl group under Fukuyama coupling
conditions15 failed, giving the b-elimination product (de-
t-Bu-12).
O
O
*
O
*
BnO
a
3
Our final plan was to use the trifluoromethyl anion as a
nucleophile (Scheme 3). The counterpart electrophile 19
was prepared in five steps from 3 by Wittig reaction (to
give 15), reduction of the formyl group (to give 16), iodo-
etherification (to give 17), deiodination (to give 18), and
oxidation. As expected, the trifluoromethyl anion ob-
tained by treatment of trimethyl(trifluoromethyl)silane
[CF3TMS] with fluoride16 attacked the aldehyde 19 to
give 8 and 8-epi-8 in 41% and 44% yield, respectively.
The undesired 8-epi-8 was converted into 8 by oxidation
(to give 14) and reduction. In a similar manner to benzyl
bishomononactate,4 SN2 reactions (mesylation–oxygen-
ation and Mitsunobu reaction) resulted in low yields.
F3C
OH
O
O
O
O
b
CF3
*
*
BnO
BnO
BnO
*
*
O
4
(EZ)-5
c
O
O
O
OH
*
*
*
*
6
(E)-5
+
3
6
*
I
3
*
I
*
*
CF3 BnO
CF3
O
O
6
7
d
O
OH
*
*
8
*
BnO
CF3
O
3
a
8 + 8-epi-8
Scheme 1 Synthetic studies toward ( )-2d. Reagents and condi-
tions: a) Ph3P+CH2CH(OH)CF3I–, BuLi, THF, –78 °C (37%, E/Z 1:1);
b) Dess–Martin periodinane, CH2Cl2 (36%); c) I2, NaHCO3, MeCN;
d) Bu3SnH, AIBN, toluene [each 11.5% from (EZ)-5].
O
O
O
*
c
*
*
6
*
*
3
*
BnO
b
R
BnO
OH
O
R
15 R = CHO
17 R = I
d
16 R = CH2OH
18 R = H
3
O
a
d
e
*
*
*
BnO
O
O
CF3
19
O
O
*
O
O
*
*
*
f
BnO
BnO
O
OH
*
O
OH
9
12
*
*
*
*
*
8
*
*
BnO
CF3
BnO
CF3
O
O
b
e
8
8-epi-8
O
O
O
O
g
h
*
*
6
*
*
6
I
3
*
I
*
*
3
BnO
CF3
BnO
O
O
BnO
CF3
O
10
13
14
c
Scheme 3 Synthetic studies toward ( )-2d. Reagents and condi-
tions: a) Ph3P=CHCHO, toluene, 95 °C (E only); b) NaBH4,
CeCl3·7H2O, MeOH (57% from 3); c) I2, NaHCO3, MeCN, –20 °C
(79%, 3,6-cis only); d) Bu3SnH, AIBN, CH2Cl2 (87%); e) Dess–
Martin periodinane, CH2Cl2, 0 °C; f) CF3TMS, TBAF (cat.), THF
(41% for 8 and 44% for 8-epi-8, from 18); g) TPAP, NMO, 4 Å MS,
CH2Cl2; h) NaBH4, MeOH (18%, two steps).
O
O
O
*
*
6
*
*
*
*
*
3
*
BnO
CF3
BnO
BnO
CF3
O
O
11
14
O
OH
Optical resolution of 8 was performed as previously re-
ported (Scheme 4).4b,c (S)-O-Acetylmandelates (+)-20
and (+)-2,3,6,8-epi-20 were easily separated by open sili-
ca gel column chromatography [Rf = 0.37 for (+)-20 and
*
CF3
O
8
Scheme 2 Synthetic studies toward ( )-2d. Reagents and condi-
tions: a) Ph3P+CH2CH2CF3I–, BuLi, Et2O, –40 to 20 °C (14%, Z only); 0.42 for (+)-2,3,6,8-epi-20 on silica gel TLC (hexane–
b) I2, NaHCO3, MeCN (86%, 3,6-cis only); c) t-BuOK, DMSO
EtOAc, 3:1)]. Fortunately, (+)-2,3,6,8-epi-20 crystallized
from hexane as colorless crystals, and X-ray crystallo-
graphic analysis (Figure 2) revealed its absolute configu-
(quant, E only); d) Ph3P+MeI–, BuLi, Et2O, –10 °C (45%); e) I2,
NaHCO3, MeCN (72%, 3,6-cis only).
ration. The relative configuration of 8 and 8-epi-8 was
Synthesis 2011, No. 22, 3741–3748 © Thieme Stuttgart · New York

PAPER
Synthesis of the Enantiomers of w-Trifluorononactic Acid
3743
(dF –64 ppm) as internal standards. Mass spectra were recorded with
a Jeol JMS-700 spectrometer. Merck silica gel 60 (70–230 mesh)
was used for column chromatography. Merck silica gel 60 F254
(0.50-mm thickness) was used for preparative TLC.
also clarified. Finally, hydrolysis of the two diesters af-
forded (+)- and (–)-w-trifluorononactic acid (2d), respec-
tively. These acids were purified as their benzyl esters 8.
8
Benzyl (2RS,3RS,6EZ)-3-tert-Butoxy-9,9,9-trifluoro-8-hydroxy-
2-methylnon-6-enoate [(EZ)-5]
a
A 50-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a N2 inlet adapter, and a septum was placed under
a N2 atmosphere. The flask was charged with triphenyl(3,3,3-triflu-
oro-2-hydroxypropyl)phosphonium iodide (806 mg, 1.65 mmol) in
anhyd THF (12 mL) and cooled to –78 °C. To this solution, 1.6 M
BuLi in hexane (2.1 mL, 3.4 mmol) was added and the mixture was
stirred for 1 h. Reddish-yellow ylide formed and to this was added
a soln of 3 (335 mg, 1.09 mmol) in THF (5 mL). The solution was
warmed to r.t. and stirred for 10 h. The solvent was evaporated and
the residue was chromatographed on silica gel (hexane–EtOAc, 5:1)
to give (EZ)-5.
AcO
O
Ph
O
AcO
O
Ph
O
O
O
BnO
CF3
BnO
CF3
O
(+)-20
b
O
(+)-2,3,6,8-epi-20
b
Yield: 161 mg, 0.40 mmol (37%); pale yellow oil; Rf = 0.41 (hex-
ane–EtOAc, 3:1).
O
OH
O
OH
IR (film): 3447 (w, OH), 2973 (s), 2930 (m), 1733 (s, C=O), 1457
(m), 1364 (m), 1266 (m), 1167 (s), 1126 (s), 1046 (m), 697 (s) cm–1.
RO
CF3
RO
CF3
O
O
(–)-2d R = H
(–)-8 R = Bn
(+)-2d R = H
(+)-8 R = Bn
1H NMR (300 MHz): d = 1.13 (m, 3 H, 2-Me), 1.18 (s, 9 H, t-Bu),
1.25–1.60 (m, 2 H), 2.00–2.30 (m, 2 H), 2.76–2.88 (m, 1 H, 2-H),
3.86–3.94 (m, 1 H, 3-H), 4.30–4.40 (m, 0.5 H, 8-H), 4.64–4.78 (m,
0.5 H, 8-H), 5.06–5.20 (m, 2 H, CH2Ph), 5.39–5.53 (m, 1 H), 5.72–
5.93 (m, 1 H), 7.26–7.43 (m, 5 H, Ph).
HRMS–FAB: m/z [M + H]+ calcd for C21H30F3O4: 403.2096; found:
403.2102.
c
c
Scheme 4 Synthesis of optically active w-trifluorononactic acid.
Reagents and conditions: a) (S)-O-acetylmandelic acid, EDCI⋅HCl,
DMAP, CH2Cl2 [quant for (+)-20 and 99% for (+)-2,3,6,8-epi-20]; b)
1 M aq KOH, THF, MeOH; c) BnBr, t-BuOK, DMF [70% for (–)-8
and 92% for (+)-8].
Benzyl (2RS,3RS,6SR,7SR)-3,6-Epoxy-9,9,9-trifluoro-8-hy-
droxy-7-iodo-2-methylnonanoate (7)
A 20-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a N2 inlet adapter, and a septum was placed under
a N2 atmosphere. The flask was charged with I2 (267 mg, 1.05
mmol) and NaHCO3 (176 mg, 2.10 mmol) in anhyd MeCN (2 mL)
and cooled to 0 °C. After the addition of (EZ)-5 (84 mg, 0.21
mmol), the solution was warmed to r.t. and stirred for 7.5 h. Then,
the mixture was diluted with sat. Na2S2O3 soln and the aqueous lay-
er was extracted with EtOAc. The combined extract was washed
with brine, dried (MgSO4), and concentrated under reduced pres-
sure to give a mixture of 7 and (E)-5 (total 76 mg). The mixture was
used in the deiodination step without further purification. Part of the
mixture was purified to give 7.
Colorless oil; Rf = 0.30 (hexane–EtOAc, 3:1).
Figure 2 Stereochemistry of (+)-2,3,6,8-epi-20 by X-ray crystallo-
IR (film): 3480 (w, OH), 1734 (s, C=O), 1264 (m), 1170 (s), 744
(m) cm–1.
graphic analysis
1H NMR (300 MHz): d = 1.18 (d, J = 6.9 Hz, 3 H, 2-Me), 1.77–2.12
(m, 4 H, 4,5-H), 2.73 (dq, J = 8.2, 6.9 Hz, 1 H, 2-H), 3.32 (d, J = 5.2
Hz, 1 H, OH), 3.73–3.83 (m, 1 H), 4.06–4.23 (m, 1 H), 4.41 (dd,
J = 3.3, 1.9 Hz, 1 H, 7-H), 5.09–5.20 (m, 1 H, 8-H), 5.13 (d, J = 12.6
Hz, 1 H, CHHPh), 5.20 (d, J = 12.6 Hz, 1 H, CHHPh), 7.26–7.40
(m, 5 H, Ph).
In conclusion, synthesis of the novel designed nonactic
acid analogues, (+)- and (–)-w-trifluorononactic acid, was
achieved. The key steps were a nucleophilic addition of
trifluoromethyl anion to aldehyde 19 and optical resolu-
tion of the product using (S)-O-acetylmandelic acid. As-
sembly of tetramer (macrotetrolide b) from these nonactic
acid analogues is under investigation.
MS (FAB): m/z = 473 [M + H]+.
Benzyl (2RS,3RS)-3-tert-Butoxy-9,9,9-trifluoro-2-methyl-8-ox-
onon-6-enoate (4)
Melting points were measured on a Yanako MP-J3 apparatus and
are uncorrected. Optical rotation values were determined using a
Horiba SEPA-300 polarimeter. FT-IR spectra were recorded as
A 10-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a N2 inlet adapter, and a septum was placed under
a N2 atmosphere. The flask was charged with 5 (25 mg, 0.062
mmol) in anhyd CH2Cl2 (2 mL) and cooled to 0 °C. To this solution,
Dess–Martin periodinane (102 mg, 0.24 mmol) was added and the
mixture was stirred for 30 min. Then, the mixture was warmed to
r.t. and stirred for 24 h. The reaction mixture was quenched with sat.
films with a Jasco 4100 spectrometer (ATR, ZnSe). 1H, 13C, and 19
F
NMR spectra were recorded in CDCl3 with a Varian Gemini 2000
1
(300 MHz for H, 75 MHz for 13C), VNMRS-600 (151 MHz for
13C), or Inova 500 (470 MHz for 19F) spectrometer with tetrameth-
ylsilane (dH 0 ppm), CHCl3 (dC 77 ppm), and a,a,a-trifluorotoluene
Synthesis 2011, No. 22, 3741–3748 © Thieme Stuttgart · New York

3744
K. Takai et al.
PAPER
aq Na2S2O3 soln and the aqueous layer was extracted with EtOAc.
The combined extract was washed with brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was chromato-
graphed on silica gel (hexane–EtOAc, 7:1) to give 4. This com-
pound is unstable.
MS (EI): m/z = 456 [M+], 428, 365 [M – Bn]+, 322, 293, 177, 165,
164, 137, 107, 91, 57.
HRMS (EI): m/z [M+] calcd for C17H20F3IO3: 456.0409; found:
456.0413.
Yield: 9.0 mg, 0.022 mmol (36%); pale yellow oil; Rf = 0.62 (hex-
ane–EtOAc, 3:1).
Benzyl (2RS,3RS,6SR,7E)-3,6-Epoxy-9,9,9-trifluoro-2-methyl-
non-7-enoate (11)
A 20-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a N2 inlet adapter, and a septum was placed under
a N2 atmosphere. The flask was charged with t-BuOK (3 mg, 0.02
mmol) in anhyd DMSO (0.5 mL). To this solution was added 10 (11
mg, 0.024 mmol) in anhyd DMSO (1.0 mL) and the mixture was
stirred for 1 h at r.t. The reaction mixture was quenched with sat.
NH4Cl soln and extracted with EtOAc. The combined extract was
washed with brine, dried (MgSO4), and concentrated under reduced
pressure. The residue was chromatographed on silica gel (hexane–
EtOAc, 7:1) to give 11.
1H NMR (300 MHz): d = 1.14 (d, J = 7.2 Hz, 3 H, 2-Me), 1.19 (s, 9
H, t-Bu), 1.3–1.8 (m, 2 H, 4-H), 2.19–2.45 (m, 2 H, 5-H), 2.82 (dq,
J = 7.1, 5.7 Hz, 1 H, 2-H), 3.93 (ddd, J = 8.2, 5.5, 3.6 Hz, 1 H, 3-H),
5.09 (d, J = 12.4 Hz, 1 H, CHHPh), 5.18 (d, J = 12.4 Hz, 1 H, CHH-
Ph), 6.35 (d, J = 15.7 Hz, 1 H, 7-H), 7.21–7.32 (m, 1 H, 6-H), 7.26–
7.43 (m, 5 H, Ph).
19F NMR (470 MHz): d = –78.768 (s).
Benzyl (2RS,3RS,6Z)-3-tert-Butoxy-9,9,9-trifluoro-2-methyl-
non-6-enoate (9)
Yield: 8.0 mg, 0.024 mmol (quant); pale yellow oil; Rf = 0.18 (hex-
A 10-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a N2 inlet adapter, and a septum was placed under
a N2 atmosphere. The flask was charged with triphenyl(3,3,3-tri-
fluoropropyl)phosphonium iodide (97 mg, 0.22 mmol) in Et2O (2
mL) and cooled to –40 °C. To this solution was added 1.6 M BuLi
in hexane (0.14 mL, 0.22 mmol) and the mixture was stirred for 50
min. A reddish-yellow ylide formed and a soln of 3 (61 mg, 0.20
mmol) in Et2O (2 mL) was added to the reaction mixture. After be-
ing stirred for 2 h, the solution was warmed to r.t. and stirred over-
night. To the reaction mixture was added H2O and the solution was
extracted with EtOAc. The combined extract was washed with
brine, dried (MgSO4), and concentrated under reduced pressure.
The residue was chromatographed on silica gel (hexane–EtOAc,
10:1) to give 9.
ane–EtOAc, 5:1).
1H NMR (300 MHz): d = 1.16 (d, J = 7.1 Hz, 3 H, 2-Me), 1.58–1.75
(m, 2 H), 2.00–2.20 (m, 2 H), 2.54–2.67 (m, 1 H, 2-H), 4.16 (dt,
J = 7.5, 6.8 Hz, 1 H), 4.40–4.53 (m, 1 H), 5.13 (d, J = 12.2 Hz, 1 H,
CHHPh), 5.21 (d, J = 12.2 Hz, 1 H, CHHPh), 5.86 (ddq, J = 15.6,
1.9, 6.6 Hz, 1 H, 8-H), 6.36 (ddq, J = 15.6, 4.4, 2.2 Hz, 1 H, 7-H),
7.25–7.42 (m, 5 H, Ph).
MS (FAB): m/z = 329 [M + H]+.
MS (EI): m/z = 328 [M+], 300, 237 [M – Bn]+, 176, 165, 107, 91.
HRMS (EI): m/z [M+] calcd for C17H19F3O3: 328.1286; found:
328.1289.
Benzyl (2RS,3RS)-3-tert-Butoxy-2-methylhept-6-enoate (12)
A 10-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a N2 inlet adapter, and a septum was placed under
a N2 atmosphere. The flask was charged with methyltriphenylphos-
phonium iodide (89 mg, 0.22 mmol) in anhyd Et2O and cooled to
–10 °C. To this was added 1.6 M BuLi in hexane (0.13 mL, 0.22
mmol) and the mixture was stirred for 15 min. Reddish-yellow ylide
formed, then to this was added a soln of 3 (33 mg, 0.11 mmol) in
anhyd Et2O and the mixture was stirred for 1 h. To the reaction mix-
ture was added H2O and the aqueous layer was extracted with Et2O.
The combined extract was washed with brine, dried (MgSO4), and
concentrated under reduced pressure. The residue was chromato-
graphed on silica gel (hexane–EtOAc, 10:1) to give 12.
Yield: 12 mg, 0.031 mmol (14%); pale yellow oil; Rf = 0.56 (hex-
ane–EtOAc, 3:1).
1H NMR (300 MHz): d = 1.12 (d, J = 7.2 Hz, 3 H, 2-Me), 1.18 (s, 9
H, t-Bu), 1.30–1.56 (m, 2 H), 1.94–2.13 (m, 2 H), 2.74–2.85 (m, 3
H), 3.87–3.93 (m, 1 H, 3-H), 5.08 (d, J = 12.2 Hz, 1 H, CHHPh),
5.17 (d, J = 12.4 Hz, 1 H, CHHPh), 5.29–5.39 (m, 1 H, 7-H), 5.61
(pseudo dt, J = 10.7, 7.4 Hz, 1 H, 6-H), 7.32–7.40 (m, 5 H, Ph).
HRMS (EI): m/z [M+] calcd for C21H29F3O3: 386.2069; found:
386.2066.
Benzyl (2RS,3RS,6SR,7SR)-3,6-Epoxy-9,9,9-trifluoro-7-iodo-2-
methylnonanoate (10)
A 10-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a N2 inlet adapter, and a septum was placed under
a N2 atmosphere. The flask was charged with I2 (15 mg, 0.06 mmol),
NaHCO3 (10 mg, 0.12 mmol) and anhyd MeCN (0.5 mL). After the
suspension had been stirred for 10 min at 0 °C under N2, a soln of 9
(8.0 mg, 0.021 mmol) in anhyd MeCN (2.0 mL) was added drop-
wise at 0 °C. After being stirred for 16 h, the reaction was quenched
with sat. aq Na2S2O3 soln and brine, and the mixture was extracted
with EtOAc. The combined extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure. The residue
was chromatographed on silica gel (hexane–EtOAc, 3:1) to give 10.
Yield: 15 mg, 0.049 mmol (45%); pale yellow oil; Rf = 0.74 (hex-
ane–EtOAc, 3:1).
1H NMR (300 MHz): d = 1.12 (d, J = 7.2 Hz, 3 H, 2-Me), 1.19 (s, 9
H, t-Bu), 1.25–1.58 (m, 2 H, 4-H), 1.92–2.17 (m, 2 H, 5-H), 2.80
(dq, J = 5.2, 7.2 Hz, 1 H, 2-H), 3.92 (ddd, J = 9.1, 5.2, 3.9 Hz, 1 H,
3-H), 4.88–5.02 (m, 2 H, 7-H), 5.09 (d, J = 12.4 Hz, 1 H, CHHPh),
5.17 (d, J = 12.4 Hz, 1 H, CHHPh), 5.72 (ddt, J = 17.0, 10.4, 6.3 Hz,
1 H, 6-H), 7.25–7.42 (m, 5 H, Ph).
MS (EI): m/z = 304 [M+], 248, 220, 193, 164, 141.
HRMS (EI): m/z [M+] calcd for C19H28O3: 304.2039; found:
Yield: 8.0 mg, 0.018 mmol (86%); pale yellow oil; Rf = 0.37 (hex-
ane–EtOAc, 3:1).
304.2035.
1H NMR (300 MHz): d = 1.18 (d, J = 7.1 Hz, 3 H, 2-Me), 1.50–1.79
(m, 2 H), 1.94–2.15 (m, 2 H), 2.62–2.80 (m, 2 H, 8-H), 2.81–3.00
(m, 1 H, 2-H), 3.46–3.56 (m, 1 H), 4.08–4.26 (m, 2 H), 5.14 (d,
J = 12 Hz, 1 H, CHHPh), 5.21 (d, J = 12 Hz, 1 H, CHHPh), 7.25–
7.42 (m, 5 H, Ph).
Benzyl (2RS,3RS,6SR)-3,6-Epoxy-7-iodo-2-methylheptanoate
(13)
A 10-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a N2 inlet adapter, and a septum was placed under
a N2 atmosphere. The flask was charged with I2 (38 mg, 0.15 mmol)
and NaHCO3 (25 mg, 0.30 mmol) in anhyd MeCN (1.0 mL). After
the suspension had been stirred for 10 min at 0 °C under N2, a soln
of 12 (9.0 mg, 0.030 mmol) in anhyd MeCN (2.0 mL) was added
MS (FAB): m/z = 457 [M + H]+.
Synthesis 2011, No. 22, 3741–3748 © Thieme Stuttgart · New York

PAPER
Synthesis of the Enantiomers of w-Trifluorononactic Acid
3745
dropwise at 0 °C. After being stirred for 21 h, the reaction was
quenched with sat. aq Na2S2O3 soln and brine, and the aqueous layer
was extracted with EtOAc. The combined extract was washed with
brine, dried (MgSO4), and concentrated under reduced pressure.
The residue was chromatographed on silica gel (hexane–EtOAc,
3:1) to give 13.
CHHPh), 5.13–5.19 (d, J = 12.6 Hz, 1 H, CHHPh), 5.58–5.63 (m, 2
H, 6,7-H), 7.27–7.40 (m, 5 H, Ph).
13C NMR (75 MHz): d = 174.75, 136.25, 133.05, 129.14, 128.59,
128.20, 73.90, 71.61, 66.00, 63.72, 44.84, 31.17, 28.71, 27.83,
10.27.
HRMS–FAB: m/z [M + Na]+ calcd for C20H30NaO4: 357.2050;
found: 357.2042.
Yield: 8.0 mg, 0.021 mmol (72%); pale yellow oil; Rf = 0.35 (hex-
ane–EtOAc, 7:1).
1H NMR (300 MHz): d = 1.16 (d, J = 7.1 Hz, 3 H, 2-Me), 1.68–1.75
(m, 2 H), 1.93–2.16 (m, 2 H), 2.66 (dq, J = 8.3, 7.1 Hz, 1 H, 2-H),
3.11 (dd, J = 9.9, 7.4 Hz, 1 H, 7-H), 3.22 (dd, J = 9.9, 4.4 Hz, 1 H,
7-H), 3.94–4.06 (m, 1 H), 4.12–4.23 (pseudo q, J = 7.7 Hz, 1 H),
5.11–5.17 (d, J = 12 Hz, 1 H, CHHPh), 5.18–5.22 (d, J = 12 Hz, 1
H, CHHPh), 7.26–7.42 (m, 5 H, Ph).
MS (EI): m/z = 374 [M+], 346, 283 [M – Bn]+, 240, 211, 115, 91, 58,
43.
HRMS (EI): m/z [M+] calcd for C15H19IO3: 374.0379; found:
374.0381.
Benzyl (2RS,3RS,6SR,7SR)-3,6-Epoxy-8-hydroxy-7-iodo-2-
methyloctanoate (17)
A 200-mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a N2 inlet adapter, and a septum was placed un-
der a N2 atmosphere. The flask was charged with I2 (3.52 g, 13.9
mmol) and NaHCO3 (2.33 g, 27.70 mmol) in anhyd MeCN (30 mL).
After the suspension had been stirred for 15 min at 0 °C under N2, a
soln of 16 (925 mg, 2.77 mmol) in anhyd MeCN (8 mL) was added
dropwise at –20 °C. After being stirred for 30 min, the reaction was
quenched with sat. aq Na2S2O3 soln and brine, and the aqueous layer
was extracted with EtOAc. The combined extract was washed with
brine, dried (MgSO4), and concentrated under reduced pressure.
The residue was chromatographed on silica gel (hexane–EtOAc,
3:1) to give 17. This compound is unstable and was used in the next
step without further purification.
Benzyl(2RS,3RS,6E)-3-tert-Butoxy-2-methyl-8-oxooct-6-enoate
(15)
A 100-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a reflux condenser with a N2 inlet adapter, and a
septum was placed under a N2 atmosphere. The flask was charged
with 3 (615 mg, 2.01 mmol) and Ph3P=CHCHO (1.04 g, 3.42
mmol) in toluene (25 mL). The mixture was stirred for 18 h at
95 °C. The solvent was evaporated and the residue was chromato-
graphed on silica gel (hexane–EtOAc, 4:1) which gave a mixture of
15 and 3 (ca. 5.1:1.7, 539 mg). Part of the mixture was purified to
give 15 as a colorless oil.
1H NMR (300 MHz): d = 1.14 (d, J = 6.9 Hz, 3 H, 2-Me), 1.19 (s, 9
H, t-Bu), 1.35–1.47 (m, 1 H, 4-H), 1.54–1.66 (m, 1 H, 4-H), 2.20–
2.45 (m, 2 H, 5-H), 2.83 (dq, J = 6.9, 5.5 Hz, 1 H, 2-H), 3.90–3.97
(m, 1 H, 3-H), 5.07–5.11 (d, J = 12.6 Hz, 1 H, CHHPh), 5.17–5.23
(d, J = 12.6 Hz, 1 H, CHHPh), 6.06 (dd, J = 15.6, 7.7 Hz, 1 H, 7-H),
6.74 (dt, J = 15.6, 6.6 Hz, 1 H, 6-H), 7.24–7.41 (m, 5 H, Ph), 9.44
(d, J = 7.7 Hz, 1 H, 8-H).
Yield: 890 mg, 2.20 mmol (79%); pale yellow oil; Rf = 0.34 (tolu-
ene–EtOAc, 5:1).
1H NMR (300 MHz): d = 1.14 (d, J = 6.9 Hz, 3 H, 2-Me), 1.60–1.73
(m, 1 H), 1.81–2.05 (m, 2 H), 2.23 (dq, J = 12.7, 7.1 Hz, 1 H, 2-H),
2.53–2.65 (m, 1 H), 2.84–2.94 (dd, J = 8.0, 7.7 Hz, 1 H, OH), 3.81–
3.88 (m, 2 H), 3.92–4.01 (m, 1 H, 3-H), 4.12–4.21 (dt, J = 8.8, 6.6
Hz, 2 H, 8-H), 5.10–5.14 (d, J = 12.6 Hz, 1 H, CHHPh), 5.15–5.19
(d, J = 12.6 Hz, 1 H, CHHPh), 7.27–7.43 (m, 5 H, Ph).
Benzyl (2RS,3RS,6SR)-3,6-Epoxy-8-hydroxy-2-methyl-
octanoate (18)
A 100-mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a N2 inlet adapter, and a septum was placed un-
der a N2 atmosphere. The flask was charged with 17 (792 mg, 1.96
mmol) in anhyd CH2Cl2 (20 mL). To this solution were added
Bu3SnH (790 mL, 2.94 mmol) and AIBN (33 mg, 0.2 mmol), and the
mixture was stirred at r.t. for 6.5 h. The mixture was further stirred
for 3 h after KF (ca. 100 mg) was added. The reaction mixture was
filtered, and the filtrate was concentrated and chromatographed on
silica gel (hexane–EtOAc, 3:1) to give 18.
HRMS–FAB: m/z [M + Na]+ calcd for C20H28NaO4: 355.1885;
found: 355.1894.
Benzyl (2RS,3RS,6E)-3-tert-Butoxy-8-hydroxy-2-methyloct-6-
enoate (16)
A 200-mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a N2 inlet adapter, and a septum was placed un-
der a N2 atmosphere. The flask was charged with the mixture of 15
and 3 (539 mg) in MeOH (50 mL). To this solution was added
CeCl3·7H2O (905 mg, 2.43 mmol) at 0 °C and the mixture was
stirred for 5 min. Then, to this was added NaBH4 (92 mg, 2.4 mmol)
and the mixture was stirred for a further 15 min. The reaction mix-
ture was diluted with sat. aq NH4Cl soln and concentrated under re-
duced pressure, and the residue was extracted with EtOAc. The
combined extract was washed with brine, dried (MgSO4), and con-
centrated under reduced pressure. The residue was chromato-
graphed on silica gel (hexane–EtOAc, 5:1) to give 16.
Yield: 477 mg, 1.71 mmol (87%); pale yellow oil; Rf = 0.21 (hex-
ane–EtOAc, 1:1).
IR (film): 3483 (w, OH), 2955 (m), 2944 (m), 2877 (m), 1734 (s,
C=O), 1498 (w), 1457 (m), 1385 (w), 1254 (w), 1185 (m), 1058 (m),
739 (w), 698 (w) cm–1.
1H NMR (300 MHz): d = 1.15 (d, J = 7.1 Hz, 3 H, 2-Me), 1.50–1.70
(m, 2 H, 4,5-H), 1.70–1.83 (m, 2 H, 7-H), 1.92–2.08 (m, 2 H, 4,5-
H), 2.54–2.70 (m, 2 H, 2-H, OH), 3.74 (t, J = 5.5 Hz, 2 H, 8-H),
3.98–4.12 (m, 2 H, 3,6-H), 5.10–5.16 (d, J = 12 Hz, 1 H, CHHPh),
5.17–5.21 (d, J = 12 Hz, 1 H, CHHPh), 7.26–7.44 (m, 5 H, Ph).
13C NMR (75 MHz): d = 174.69, 136.10, 128.54, 128.21, 128.16,
81.07, 79.46, 66.20, 61.27, 45.31, 37.61, 31.02, 28.65, 28.39, 13.27.
HRMS–FAB: m/z [M + H]+ calcd for C16H23O4: 279.1598; found:
279.1597.
Yield: 400 mg, 1.20 mmol (57%, two steps from 3); pale yellow oil;
Rf = 0.20 (hexane–EtOAc, 3:1).
IR (film): 3448 (w, OH), 2974 (s), 2930 (s), 2850 (m), 1734 (s,
C=O), 1457 (m), 1364 (m), 1254 (m), 1190 (m), 1050 (m), 748 (w),
698 (w) cm–1.
1H NMR (300 MHz): d = 1.12 (d, J = 7.1 Hz, 3 H, 2-Me), 1.18 (s, 9
H, t-Bu), 1.27–1.42 (m, 1 H), 1.43–1.58 (m, 1 H), 1.92–2.16 (m, 2
H), 2.74–2.85 (quintet, J = 7.1 Hz, 1 H, 2-H), 3.87–3.94 (m, 1 H, 3-
H), 4.01–4.08 (m, 2 H, 8-H), 5.06–5.12 (d, J = 12.6 Hz, 1 H,
Benzyl (2RS,3RS,6SR,8RS)-3,6-Epoxy-9,9,9-trifluoro-8-hy-
droxy-2-methylnonanoate (Benzyl w-Trifluorononactate, 8)
and 8-epi-8
A 200-mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a N2 inlet adapter, and a septum was placed un-
der a N2 atmosphere. The flask was charged with Dess–Martin per-
Synthesis 2011, No. 22, 3741–3748 © Thieme Stuttgart · New York

3746
K. Takai et al.
PAPER
iodinane (2.80 g, 6.54 mmol) in anhyd CH2Cl2. To this solution was
added 18 (909 mg, 3.27 mmol) in anhyd CH2Cl2 (10 mL) at 0 °C
and the mixture was stirred for 2.5 h. The reaction mixture was
poured into sat. aq Na2S2O3 soln and sat. aq NaHCO3 soln, and ex-
tracted with EtOAc. The combined extract was washed with brine,
dried (MgSO4), and concentrated under reduced pressure to give al-
dehyde 19. This aldehyde is unstable and was used in the next step
without further purification.
lution was stirred for 2.5 h at r.t. The reaction mixture was filtered
through a Celite® pad and the filtrate was concentrated under re-
duced pressure to give 14. This ketone was used in the next reduc-
tion step without further purification.
Yield: 26 mg; pale yellow oil; Rf = 0.34 (toluene–EtOAc, 5:1).
A 30-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar was charged with 14 (26 mg) in MeOH (2 mL). To
this solution was added NaBH4 (25 mg, 0.66 mmol) and the mixture
was stirred for 30 min at r.t. Then, the reaction mixture was diluted
with sat. aq NH4Cl soln and concentrated under reduced pressure.
The residue was extracted with EtOAc and the combined extract
was washed with brine, dried (MgSO4), and concentrated under re-
duced pressure. The residue was chromatographed on silica gel
(hexane–EtOAc, 10:1) to give 8.
Yield: 933 mg; pale yellow oil.
1H NMR (300 MHz): d = 1.14 (d, J = 6.9 Hz, 3 H, 2-Me), 1.45–1.80
(m, 2 H), 1.91–2.20 (m, 2 H), 2.47–2.72 (m, 3 H), 4.09 (dt, J = 8.2,
7.2 Hz, 1 H, 3-H), 4.30 (pseudo quintet, J = 6.6 Hz, 1 H, 6-H), 5.09–
5.14 (d, J = 12.4 Hz, 1 H, CHHPh), 5.16–5.20 (d, J = 12.4 Hz, 1 H,
CHHPh), 7.22–7.42 (m, 5 H, Ph), 9.73 (t, J = 2.2 Hz, 1 H, 8-H).
A 200-mL three-necked round-bottomed flask equipped with a
magnetic stirrer bar, a N2 inlet adapter, and a septum was placed un-
der a N2 atmosphere. The flask was charged with 19 (933 mg, 3.38
mmol) in anhyd THF (65 mL). To this solution were added
CF3TMS (0.750 mL, 5.07 mmol) and 1 M TBAF in THF (0.40 mL,
0.40 mmol) at 0 °C, and the mixture was stirred for 10 min. The
mixture was further stirred for 15 min at 0 °C after 1 M aq HCl was
added. The reaction mixture was poured into sat. aq NH4Cl soln and
extracted with EtOAc. The combined extract was washed with
brine, dried (MgSO4), and concentrated under reduced pressure.
The residue was chromatographed on silica gel (hexane–EtOAc,
20:1) which gave 8 and 8-epi-8.
Yield: 8.0 mg, 0.023 mmol (18%, two steps from 8-epi-8); pale yel-
low oil.
(+)-Benzyl (2S,3S,6R,8S)-8-[(2S)-2-Acetoxy-2-phenylacetoxy]-
3,6-epoxy-9,9,9-trifluoro-2-methylnonanoate [(+)-20] and (+)-
2,3,6,8-epi-20
A 50-mL three-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a N2 inlet adapter, and a septum was placed under
a N2 atmosphere. The flask was charged with 8 (300 mg, 0.867
mmol) in CH2Cl2 (18 mL). To this solution were added (S)-O-
acetylmandelic acid (254 mg, 1.31 mmol), EDCI·HCl (250 mg, 1.31
mmol), and DMAP (12 mg, 0.1 mmol), and the mixture was stirred
at r.t. for 1 h. The reaction mixture was poured into sat. aq NH4Cl
soln and extracted with EtOAc. The combined extract was washed
with brine, dried (MgSO4), and concentrated under reduced pres-
sure. The residue was chromatographed on silica gel (hexane–
EtOAc, 20:1) which gave (+)-20 and (+)-2,3,6,8-epi-20.
8
Yield: 468 mg, 1.35 mmol (41% from 18); pale yellow oil; Rf = 0.38
(hexane–EtOAc, 1:1).
IR (film): 3434 (w, OH), 2955 (w), 2939 (w), 2870 (w), 1734 (s,
C=O), 1498 (w), 1457 (w), 1385 (w), 1276 (s), 1163 (s), 1127 (s),
1072 (s), 860 (w), 739 (w), 698 (w), 575 (w) cm–1.
1H NMR (300 MHz): d = 1.15 (d, J = 7.1 Hz, 3 H, 2-Me), 1.52–1.82
(m, 3 H), 1.84–1.95 (m, 1 H), 1.96–2.10 (m, 2 H), 2.56 (quintet,
J = 7.1 Hz, 1 H, 2-H), 3.38 (d, J = 5.5 Hz, 1 H, OH), 4.01–4.24 (m,
3 H, 3,6,8-H), 5.08–5.12 (d, J = 12 Hz, 1 H, CHHPh), 5.15–5.19 (d,
J = 12 Hz, 1 H, CHHPh), 7.27–7.44 (m, 5 H, Ph).
(+)-20
Yield: 226 mg, 0.433 mmol (quant); pale yellow oil; [a]D24 +16 (c
0.27, CHCl3); Rf = 0.37 (hexane–EtOAc, 3:1).
IR (film): 2979 (w), 2948 (w), 1776 (m, C=O), 1739 (s, C=O), 1497
(w), 1455 (w), 1375 (w), 1281 (w), 1231 (m), 1182 (m), 1062 (m),
739 (w), 698 (w) cm–1.
1H NMR (300 MHz): d = 1.12 (d, J = 7.2 Hz, 3 H, 2-Me), 1.40–1.70
(m, 2 H), 1.88 (t, J = 6.6 Hz, 2 H), 1.91–2.06 (m, 2 H), 2.20 (s, 3 H,
Ac), 2.57 (quintet, J = 7.2 Hz, 1 H, 2-H), 3.85 (pseudo quintet,
J = 6.5 Hz, 1 H, 3/6-H), 4.03 (pseudo q, J = 7.0 Hz, 1 H, 6/3-H),
5.10–5.14 (d, J = 12.6 Hz, 1 H, CHHPh), 5.15–5.19 (d, J = 12.6 Hz,
1 H, CHHPh), 5.50 (sextet, J = 6.5 Hz, 1 H, 8-H), 5.94 (s, 1 H,
AcOCH), 7.25–7.46 (m, 10 H, 2 Ph).
13C NMR (75 MHz): d = 174.63, 136.07, 128.58, 128.34, 128.25,
127.4 (q, J = 278 Hz, 9-C), 81.20, 75.40, 67.91 (q, J = 31.5 Hz, 8-
C), 66.27, 45.44, 34.65, 30.63, 28.49, 13.42.
19F NMR (470 MHz): d = –80.599 (d, J = 7.52 Hz).
HRMS–FAB: m/z [M + H]+ calcd for C17H22F3O4: 347.1470; found:
347.1470.
13C NMR (75 MHz): d = 172.14, 170.44, 167.37, 129.53, 128.86,
128.55, 128.24, 128.14, 127.59, 124.00 (q, J = 285 Hz, 9-C), 80.53,
75.85, 74.19, 74.11, 68.55 (q, J = 29 Hz, 8-C), 66.19, 45.21, 34.21,
30.97, 28.30, 20.47, 12.94.
19F NMR (470 MHz): d = –79.064 (d, J = 6.11 Hz).
HRMS–FAB: m/z [M + H]+ calcd for C27H30F3O7: 523.1944; found:
8-epi-8
Yield: 496 mg, 1.43 mmol (44% from 18); pale yellow oil; Rf = 0.41
(hexane–EtOAc, 1:1).
1H NMR (300 MHz): d = 1.15 (d, J = 6.9 Hz, 3 H, 2-Me), 1.54–1.79
(m, 3 H), 1.90–2.15 (m, 3 H), 2.54–2.65 (quintet, J = 7.1 Hz, 1 H,
2-H), 4.05–4.17 (m, 3 H), 5.08–5.13 (d, J = 12.3 Hz, 1 H, CHHPh),
5.15–5.20 (d, J = 12.3 Hz, 1 H, CHHPh), 7.26–7.40 (m, 5 H, Ph).
523.1952.
MS (EI): m/z = 346 [M+], 255 [M – Bn]+, 237, 212, 194, 183, 170,
139, 122, 105, 91, 85, 55, 28.
HRMS (EI): m/z [M+] calcd for C17H21F3O4: 346.1392; found:
346.1395.
(+)-2,3,6,8-epi-20
Yield: 223 mg, 0.427 mmol (99%); colorless crystals (recrystallized
from hexane); mp 114–115 °C; [a]D +47 (c 0.51, CHCl3);
Rf = 0.42 (hexane–EtOAc, 3:1).
24
IR (film): 2951 (s), 2825 (s), 1781 (m, C=O), 1743 (s, C=O), 1382
(w), 1256 (m), 1188 (m), 1059 (s), 1033 (s), 800 (m) cm–1.
1H NMR (300 MHz): d = 1.07 (d, J = 6.6 Hz, 3 H, 2-Me), 1.14–1.28
(m, 2 H), 1.42–1.64 (m, 2 H), 1.67–1.76 (m, 2 H), 2.19 (s, 3 H, Ac),
2.48 (quintet, J = 7.4 Hz, 1 H, 2-H), 3.01 (quintet, J = 6.6 Hz, 1 H,
3/6-H), 3.74 (q, J = 7.2 Hz, 1 H, 6/3-H), 5.11–5.15 (d, J = 12.3 Hz,
Conversion of 8-epi-8 into 8
A 30-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a N2 inlet adapter, and a septum was placed under
a N2 atmosphere. The flask was charged with 8-epi-8 (44 mg, 0.13
mmol), NMO (39 mg, 0.33 mmol), and 4 Å MS (30 mg) in anhyd
CH2Cl2 (2 mL). After TPAP (5 mg, 0.01 mmol) was added, the so-
Synthesis 2011, No. 22, 3741–3748 © Thieme Stuttgart · New York

PAPER
Synthesis of the Enantiomers of w-Trifluorononactic Acid
3747
24
1 H, CHHPh), 5.16–5.20 (d, J = 12.3 Hz, 1 H, CHHPh), 5.49 (sex-
tet, J = 6.8 Hz, 1 H, 8-H), 5.98 (s, 1 H, AcOCH), 7.27–7.48 (m, 10
H, 2 Ph).
13C NMR (75 MHz): d = 174.50, 170.21, 167.10, 136.22, 133.46,
129.50, 128.86, 128.57, 128.34, 128.17, 123.50 (q, J = 282 Hz, 9-
C), 80.33, 74.06, 73.25, 68.29 (q, J = 33.2 Hz, 8-C), 66.27, 45.08,
33.71, 30.64, 28.15, 20.50, 12.95.
Yield: 77 mg, 0.22 mmol (70%); pale yellow oil; [a]D –0.45 (c
0.55, CHCl3).
MS (EI): m/z = 346 [M+], 255 [M – Bn]+, 237, 212, 194, 183, 170,
139, 107, 91, 85, 83, 55, 43.
HRMS (EI): m/z [M+] calcd for C17H21F3O4: 346.1392; found:
346.1390.
19F NMR (470 MHz): d = –78.807 (d, J = 6.11 Hz).
HRMS–FAB: m/z [M + H]+ calcd for C27H30F3O7: 523.1944; found:
(+)-2d
A 30-mL one-necked round-bottomed flask equipped with a mag-
netic stirrer bar was charged with (+)-2,3,6,8-epi-20 (90 mg, 0.17
mmol) in MeOH (1 mL) and THF (3 mL). To this solution was add-
ed 1 M aq KOH (4 mL) at 0 °C and the mixture was stirred for 24
h. Then, the solvent was evaporated and the residue was washed
with CHCl3. The aqueous layer was acidified with 1 M HCl and ex-
tracted with EtOAc. The combined extract was washed with brine,
dried (MgSO4), and concentrated under reduced pressure to give
crude (+)-2d (71 mg) as a pale yellow oil. This carboxylic acid was
used in the next step without further purification. An analytical sam-
ple was further purified.
523.1941.
X-ray Crystallographic Analysis of (+)-2,3,6,8-epi-20
Colorless crystals (C27H29F3O7) were recrystallized from hexane,
and the data were collected by using a Rigaku AFC7R diffractome-
ter with Mo Ka radiation and a rotating anode generator. Calcula-
tions were performed using the teXsan software package from
Molecular Structure Corporation. The structure was solved by a di-
rect method (SIR92) and expanded using Fourier techniques
(DIRDIF94).
Colorless oil; [a]D24 +3.3 (c 0.50, CHCl3).
HRMS–FAB: m/z [M + H]+ calcd for C10H16F3O4: 257.1000; found:
CCDC 823244 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
257.0999.
(+)-8
(–)-(2S,3S,6R,8S)-3,6-Epoxy-9,9,9-trifluoro-8-hydroxy-2-meth-
ylnonanoic Acid [w-Trifluorononactic Acid, (–)-2d]
A 50-mL two-necked round-bottomed flask equipped with a mag-
netic stirrer bar, a N2 inlet adapter, and a septum was placed under
a N2 atmosphere. The flask was charged with t-BuOK (63 mg, 0.56
mmol) in anhyd DMF (6 mL). To this solution was added the crude
(+)-2d in anhyd DMF (2 mL) and the mixture was then warmed to
60 °C and stirred for 5 min. To this was added BnBr (70 mL, 0.59
mmol) and the mixture was stirred for 20 h. The reaction mixture
was diluted with EtOAc, and washed with H2O and brine. The or-
ganic layer was dried (MgSO4) and concentrated under reduced
pressure. The residue was chromatographed on silica gel (hexane–
EtOAc, 10:1) to give (+)-8.
A 100-mL one-necked round-bottomed flask equipped with a mag-
netic stirrer bar was charged with (+)-20 (167 mg, 0.320 mmol) in
MeOH (3 mL) and THF (4 mL). To this solution was added 1 M aq
KOH (6 mL) at 0 °C and the mixture was stirred for 24 h. Then, the
solvent was evaporated and the residue was washed with CHCl3.
The aqueous layer was acidified with 1 M aq HCl and extracted with
EtOAc. The combined extract was washed with brine, dried
(MgSO4), and concentrated under reduced pressure to give crude
(–)-2d (135 mg) as a pale yellow oil. An analytical sample was fur-
ther purified.
24
Yield: 55 mg, 0.16 mmol (92%); pale yellow oil; [a]D +0.56 (c
Colorless oil; [a]D24 –3.5 (c 0.71, CHCl3).
0.90, CHCl3).
IR (film): 3415 (s, OH), 2962 (s), 1713 (s, C=O), 1277 (s), 1165 (s),
1128 (s), 1070 (s) cm–1.
HRMS–FAB: m/z [M + H]+ calcd for C17H22F3O4: 347.1469; found:
347.1472.
1H NMR (300 MHz): d = 1.16 (d, J = 6.8 Hz, 3 H, Me), 1.60–1.80
(m, 3 H, 4,5-H), 1.88 (ddd, J = 13.5, 10.1, 3.0 Hz, 1 H), 2.00–2.20
(m, 2 H, 7-H), 2.46 (quintet, J = 6.8 Hz, 1 H, 2-H), 4.00–4.13 (m, 1
H), 4.14–4.40 (m, 2 H), 5.9–7.2 (br, 1 H, CO2H).
13C NMR (151 MHz): d = 179.53, 125.31 (q, J = 282 Hz, 9-C),
81.59, 75.16, 67.22 (q, J = 31.4 Hz, 8-C), 46.34, 35.21, 30.72,
29.00, 13.78.
Acknowledgment
Financial support by a grant-in-aid from the Japan Society for the
Promotion of Science (No. 17580092 and 19580120), The Agricul-
tural Chemical Research Foundation, the Intelligent Cosmos Foun-
dation, and The Naito Foundation is gratefully acknowledged.
19F NMR (470 MHz): d = –80.901 (d, J = 10.8 Hz).
HRMS–FAB: m/z [M + H]+ calcd for C10H16F3O4: 257.1000; found:
References
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A 50-mL two-necked round-bottomed flask equipped with a mag-
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a N2 atmosphere. The flask was charged with t-BuOK (119 mg, 1.06
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