New synthetic approach to mevalonate and mevaldate fluoroanalogues

Article abstract of DOI:10.1016/j.tetasy.2007.08.015

6,6,6-Tri- and 6,6-difluoromevalonate were synthesized by new method starting from the corresponding β-alkoxyvinyl polyfluoromethyl ketones. Enantiomers of fluoromevalonates were obtained by column chromatography separation of diastereomeric (S)-(-)-1-phe

Full text of DOI:10.1016/j.tetasy.2007.08.015

Tetrahedron: Asymmetry 18 (2007) 1918–1925
New synthetic approach to mevalonate and mevaldate fluoroanalogues
Ivan S. Kondratov,a,* Igor I. Gerus,a Valery P. Kukhara and Olga V. Manoilenkob
aInstitute of Bioorganic Chemistry and Petrochemistry, National Ukrainian Academy of Science, Murmanska 1, Kiev-94, 02660, Ukraine
bDepartment of Chemistry, Kyiv Taras Shevchenko University, Volodymyrska Street, 64, Kyiv 01033, Ukraine
Received 27 June 2007; accepted 13 August 2007
Abstract—6,6,6-Tri- and 6,6-difluoromevalonate were synthesized by new method starting from the corresponding b-alkoxyvinyl
polyfluoromethyl ketones. Enantiomers of fluoromevalonates were obtained by column chromatography separation of diastereomeric
(S)-(ꢀ)-1-phenylethylamides of fluoromevalonates with the following hydrolysis. Racemic 6,6,6-tri- and 6,6-difluoromevaldates were also
prepared.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
a mevalonate pathway, namely the mevalonate transforma-
tion to isopentenyl pyrophosphate; monofluoromevalo-
nate 3c was found as the most effective inhibitor (Ki =
10 nM).3c,4
Mevalonate (mevalonic acid) 1 and mevaldate 2 (mevaldic
acid) (Fig. 1) are important secondary metabolites in the
biosynthesis of such important bioregulators as cholesterol,
dolichol, ubiquinone, vitamin D, and others.1 Therefore,
the synthesis and biochemical investigation of the fluori-
nated analogues of these compounds are of interest because
replacement of hydrogen by fluorine in natural compounds
molecules often leads to biologically active compounds.2
Previously, several fluorinated mevalonate analogues, such
as 6,6,6-trifluoromevalonate 3a, 6,6-difluoromevalonate
3b, 6-monofluoromevalonate 3c, and 4,4-difluoromevalo-
nate 4 and some of their derivatives, were synthesized as
racemates.3 They were shown to be efficient inhibitors of
Inhibition of isopentenyl pyrophosphate synthesis by fluoro-
mevalonates leads to various biological effects. Hence it
was shown that fluorinated mevalonates effectively block
insect juvenile hormones synthesis.3b,5 Monofluoromevalo-
nate also shows anticancer activity, which is caused by
p21ras oncoprotein synthesis blocking.6 Moreover, mono-
fluoromevalonate was used in some investigations of bio-
chemical and physiological processes, where mevalonic
acid plays an important role.7
In spite of the fact that fluorocontaining mevalonates are
interesting as biologically active compounds, there are only
a few articles, which pay attention to the synthesis of these
compounds.3 Moreover, there is no information with
regards to obtaining enantiomerically pure fluoromevalo-
nates (except for single report on the detection of mono-
fluoromevalonate 3c enantiomers by resolution on
analytical chiral GLC)8 although a configuration of these
molecules is probably important because only the (R)-
enantiomer of mevalonate 1 is found in Nature.9 More-
over, it was suggested that just one of the fluoromevalonate
enantiomers takes part in mevalonate pathway inhibition.4
At the same time fluorinated analogues of mevaldate are
unknown, although it should be expected that they are
regulators in the mevalonate pathway also, because meval-
date 2 is a precursor of mevalonic acid 1 in vivo.10
HO
HO
Rf
HO
HO
F
F
O
HO
O
O
O
O
O
O
O
1
2
3a-c
4
3a: Rf = CF3
3b: Rf = CHF2
3c: Rf = CH2F
Figure 1. Structures of natural mevalonate 1, mevaldate 2, and known
fluorinated analogues of mevalonates 3 and 4.
*
Corresponding author. Tel.: +380 44 573 2598; fax: +380 44 573 2552;
e-mail: vanya_ko@mail.ru
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.08.015

I. S. Kondratov et al. / Tetrahedron: Asymmetry 18 (2007) 1918–1925
1919
Herein, we report a new synthetic method for obtaining
6,6,6-tri- and 6,6-difluoromevalonates in both racemic
and enantimerically pure forms. We also report the synthe-
sis of racemic 6,6,6-tri- and 6,6-difluoromevaldates.
In order to carry out the first stage of fluoromevalonate
synthesis in an asymmetric manner, we carried out aldol
and Reformatsky13 reactions with chiral previously synthe-
sized CF3-enones 5c–e and ketoacetal 914 (Fig. 2). How-
ever, the diastereoselectivity of the reactions was low and
further attempts to separate diastereomers failed.
2. Results and discussion
O
O
O
The key step of our retrosynthetic scheme of fluoromevalo-
nate synthesis (Scheme 1) is C–C bond formation between
acetate enolate A and fluorinated b-ketoaldehyde deriva-
tive with protected aldehyde group B. The most available
fluorinated b-ketoaldehyde derivatives with protected alde-
hyde group are b-alkoxyvinyl polyfluoromethyl ketones 5,
which are useful building blocks for fluoroorganic synthe-
sis11 and have been investigated in our laboratory for the
synthesis of potential biologically active compounds.12
F3C
F3C
OR
O
5c-e
EtO2C
CO2Et
5c: R = rac-PhCH(CH3)
5d: R = (-)-Menthyl
5e: R = (-)-Bornyl
9
Figure 2. Chiral trifluoroacetyl acetaldehyde derivatives used in asym-
metric aldol and Reformatsky reactions.
O
-H2C
OR
O
O
HO
Rf
HO Rf
O
A
OR
Enantiomerically pure fluoromevalonates were obtained by
following enantiomer separation pathway (Scheme 3):
the reaction of rac-fluoromevalonates 3a and 3b with
(S)-(ꢀ)-1-phenylethylamine gave a mixture of diastereo-
meric amides 10a and 10b, easily separated by column
chromatography, while further acidic hydrolysis of pure
diastereomers (S,S)- and (R,S)-10a,b leads to the corres-
ponding enantiomers (S)-3a,b and (R)-3a,b.
+
O
O
O
O
O
Rf
B
O
- Aldehyde group
protection
O
In order to determine the absolute configuration of the
resolved enantiomers 3a and 3b the X-ray analysis of
6,6,6-trifluoromevalonate (ꢀ)-3b was performed and it
was determined as the (R)-enantiomer (Fig. 3).15 The same
configuration corresponds to natural (ꢀ)-mevalonate 1 and
it can be supposed that (ꢀ)-difluoromevalonate (ꢀ)-3b also
has an (R)-configuration.
Scheme 1. Retrosynthetic scheme of fluoromevalonate synthesis.
The first reaction in the proposed scheme is C–C bond for-
mation by the addition of t-butyl acetate enolate to car-
bonyl group of enone 5 to give product 6 (Scheme 2).
The next step is a mild hydrolysis of the ethoxyvinyl group
to give aldehyde 7; the t-butoxycarbonyl group does not
hydrolyze under these conditions. Aldehyde 7 can be easily
reduced by sodium triacetoxy borohydride to give diol 8. It
should be mentioned that reduction by sodium boro-
hydride, which is standard for similar transformations,
gives a poor yield of compound 8. The last stage of the
synthesis of compounds 3 is the removal of the protective
t-butoxy group with trifluoroacetic acid in dichlorometh-
ane. All intermediate compounds 6–8 can be purified by
column chromatography at each stage, although the
scheme proposed allows us to obtain fluoromevalonates
3a,b without the isolation of intermediate products in 56–
59% overall yield.
The enantiomeric purity of obtained mevalonates (S)- and
(R)-3a,b was confirmed by HPLC-analysis of crude amides
11 obtained from fluoromevalonates rac-, (S)- and (R)-3,
and (S)-(ꢀ)-ethylnaphtylamine at the same reaction condi-
tions as written above for (S)-(ꢀ)-1-phenylethylamine
(Fig. 4 illustrates HPLC-analysis for 11a). According to
these data practically 100% enantiomeric purity can be sup-
posed for mevalonates (S)- and (R)-3a,b.
The synthetic pathway to fluoromevalonates 3 (Scheme
2) can also be used for synthesis of racemic tri- and
O
HO
Rf
HO Rf
HO Rf
HO Rf
iii
iv
ii
i
Rf
O
t-BuO
O
OEt
t-BuO
O
t-BuO
O
OH
O
O
OEt
5a,b
6a,b
7a,b
8a,b
3a,b
3,5-8a:Rf = CF3
3,5-8b:Rf = CHF2
Scheme 2. Synthesis of fluorinated mevalonates 3. Reagents and conditions: (i) LDA, t-BuOAc, THF, ꢀ78 ꢁC, 79–81%; (ii) 5 M HCl, THF/H2O, 0 ꢁC,
56–61%; (iii) NaBH(OAc)3, benzene, rt, 76–79%; (iv) CF3COOH, CH2Cl2, rt, 74–81%.

1920
I. S. Kondratov et al. / Tetrahedron: Asymmetry 18 (2007) 1918–1925
HO
Rf
HO
Rf
ii
ii
HO
O
N
H
O
O
HO
Rf
NH2
(S,S)-(-)-10a,b
(S)-(+)-3a,b
i
+
O
O
HO
Rf
HO
Rf
rac-3a,b
(S)-(-)-1-phenylethylamine
HO
O
N
H
O
O
3,10a:Rf = CF3
3,10b:Rf = CHF2
(R,S)-(-)-10a,b
(R)-(-)-3a,b
Scheme 3. Fluoromevalonate enantiomers separation. Reagents and conditions: (i) (1) CH2Cl2, rt, 24 h, (2) chromatography separation (21–27% yield of
each pure diastereomer); (ii) 5 M HCl, H2O/CH3CN, reflux, 30 min, 65–75%.
HO
CF3
HO
O
N
H
11a
Figure 4. HPLC-analysis chromatograms of amides 11a obtained from (a)
S-(+)-3a; (b) racemic 3a; (c) R-(ꢀ)-3a.
Figure 3. A general view of the X-ray crystallographic structure of
compound (R)-(ꢀ)-3a.
HO Rf
HO Rf
i
difluoromevaldic acids 12a and 12b (Scheme 4), which can
be obtained from aldehydes 7a and 7b by treating with
trifluoroacetic acid in good yield.
O
t-BuO
O
O
O
OH
7a,b
12a,b
1H and 19F NMR spectra of obtained fluorinated rac-
mevaldates 12a and 12b were complicated by an equilib-
rium (Scheme 5) between two diastereomeric lactolic forms
12-I and 12-II (whose signals are obviously overlapped, see
Sections 4.4.1 and 4.4.3) and acyclic form 13 in various sol-
vents. In order to avoid the equilibrium difficulties in the
characterization of fluorinated rac-mevaldates 12a and
12b we prepared corresponding sodium salts 14a and 14b
and the NMR-spectroscopic data demonstrate only the
opened form 14.
7,12a:Rf = CF3
7,12b:Rf = CHF2
Scheme 4. Synthesis of fluorinated rac-mevaldates 12a and 12b. Reagents
and conditions: (i) CF3COOH, CH2Cl2, rt, 73–77%.
3. Conclusion
A new method for the synthesis of tri- and difluoromeval-
onates 3a and 3b and tri- and difluoromevaldates 12a and

I. S. Kondratov et al. / Tetrahedron: Asymmetry 18 (2007) 1918–1925
1921
of THF was added and the mixture obtained was stirred
at ꢀ78 ꢁC for 15 min. The solution of enone 5a (0.2 g,
1.2 mmol) in 2 mL of THF was then added. After 30 min
of stirring at ꢀ78 ꢁC, the mixture obtained was warmed
to room temperature and was stirred for 2 h. The solution
was quenched with brine, the THF phase was separated
and the water phase was extracted with ether
(3 · 10 mL). The combined organic layers were dried with
anhydrous MgSO4. The solvents were removed under
vacuum and the residue was purified by flash chromato-
graphy (hexane/ethyl acetate, 5:1, Rf = 0.62) giving 0.27 g
of the resulting product 6a as a colorless oil (81% yield).
1H NMR (CDCl3): dH 1.28 t (3H, CH2CH3, JHH = 7.0 Hz),
HO Rf
HO Rf
HO Rf
O
O
O
OH
HO
O
O
O
OH
13a,b
12-II a,b
12-I a,b
i
HO Rf
12-14a:Rf = CF3
12-14b:Rf = CHF2
Na+
-O
O
O
1.46 s (9H, C(CH3)3), 2.55 d (1H, CHHCO2Bu-t, JHH
=
15.4 Hz), 2.71 d (1H, CHHCO2Bu-t, JHH = 15.4 Hz),
3.77 q (2H, CH2CH3, JHH = 7.0 Hz), 4.75 d (1H, C–
CH@, JHH = 12.6 Hz), 5.09 s (1H, OH), 6.75 d (1H,
@CH–O, JHH = 12.6 Hz). 13C NMR (CDCl3): dC 14.6
(CH2CH3), 27.9 (C(CH3)3), 39.7 (CH2CO2Bu-t), 65.4
14a,b
Scheme 5. The equilibrium of fluoromevaldates 12a and 12b in the
solution and salts 14a and 14b obtaining. Reagents and conditions: (i)
1 equiv of NaOH, H2O, rt, 61–64%.
(CH2CH3), 73.3
q
(C–CF3, JCF = 29.8 Hz), 83.1
(C(CH3)3), 99.7 (C–CH@), 124.8 q (CF3, JCF = 285.3 Hz),
151.3 (@CH–O), 170.8 (CO2Bu-t). 19F NMR (CDCl3):
dF ꢀ82.87 s (CF3). IR (CCl4, cmꢀ1): m 3408, 2984, 2936,
1712, 1680, 1656, 1456, 1422, 1392, 1352, 1312, 1164,
1077, 1032. Anal. Calcd for C12H19F3O4: C, 50.70; H,
6.74. Found: C, 50.59; H, 6.79.
12b starting from the corresponding alkoxy enones 5a and
5b has been developed. Enantiomerically pure fluoromeval-
onates were obtained by a three step method: preparation
of diastereomeric (S)-(ꢀ)-1-phenylethylamides 10a and
10b, their chromatographic separation and hydrolysis.
The absolute configuration of (R)-(ꢀ)-6,6,6-trifluoro-
mevalonate (ꢀ)-3a was determined by X-ray analysis.
4.2.2. tert-Butyl (E)-3-(difluoromethyl)-5-ethoxy-3-hydroxy-
4-pentenoate 6b. This was synthesized by similar method-
ology as 6a from tert-butyl acetate (0.20 g, 1.72 mmol) and
enone 5b (0.18 g, 1.2 mmol) giving 0.25 g of 6b (79% yield)
1
4. Experimental
4.1. General
as a colorless oil, Rf = 0.55 (hexane/ethyl acetate, 5:1). H
NMR (CDCl3): dH 1.27 t (3H, CH2CH3, JHH = 7.1 Hz),
1.45 s (9H, C(CH3)3), 2.46 d (1H, CHHCO2Bu-t, JHH
=
15.4 Hz), 2.62 d (1H, CHHCO2Bu-t, JHH = 15.4 Hz),
3.74 q (2H, CH2CH3, JHH = 7.0 Hz), 4.60 s (1H, OH),
4.72 d (1H, C–CH@, JHH = 12.6 Hz), 5.50 dd (1H,
1
IR spectra were recorded on ‘Specord M-80’. H, 13C, and
19F NMR spectra were recorded on Varian VXR instru-
ment at 300 MHz, Varian Unian Plus at 400 MHz and
Bruker Avance DRX at 500 MHz. Chemical shifts were
reported in parts per million (ppm). TMS and CCl3F were
CHF2, JHF = 57.3, 55.6 Hz), 6.65
d (1H, @CH–O,
JHH = 12.6 Hz). 13C NMR (CDCl3): dC 14.6 (CH2CH3),
28.0 (C(CH3)3), 38.8 (CH2CO2Bu-t), 65.2 (CH2CH3), 72.7
dd (C–CHF2, JCF = 22.8, 22.2 Hz), 82.4 (C(CH3)3), 101.3
(C–CH@), 116.4 dd (CHF2, JCF = 252.6, 247.5 Hz), 150.3
(CH@CHOEt), 171.3 (CO2Bu-t). 19F NMR (CDCl3):
dF ꢀ131.88 dd (1F, CHFF, JFF = 276.6, JHF = 55.6 Hz),
ꢀ129.74 dd (1F, CHFF, JFF = 276.6, JHF = 57.3 Hz). IR
(CH2Cl2, cmꢀ1): m 3446, 3060, 2984, 2933, 1705, 1672,
1656, 1454, 1416, 1392, 1368, 1248, 1224, 1200, 1155,
1064, 952. Anal. Calcd for C12H20F2O4: C, 54.13; H,
7.57. Found: C, 54.21; H, 7.48.
used as internal standards for H (13C) and 19F, respec-
1
tively. The conversion of reactions was monitored by
TLC-plates (silica gel 60 F254, Merck). Column chromato-
graphy was carried out on silica gel 60 (Merck No. 109385,
particle size 0.040–0.063). HPLC analysis was performed
on Agilent 1100, Diode Array (DA) UV detector, wave-
length ꢀ254 nm, column ZORBAX SB-C18 5 lm,
9.4 · 250 mm, mobile phase: CH3CN/H2O. Injection vol-
ume: 10 lL. Starting materials were commercially available
(Aldrich, Fluka, Merck). All solvents and liquid reagents
were distilled before use. Starting enones 5a,11a 5b,11c chiral
enones 5c–e,14 and ketoacetal 914 were prepared according
to literature procedures.
4.2.3. tert-Butyl 3-hydroxy-5-oxo-3-(trifluoromethyl)penta-
noate 7a. An aqueous solution of hydrochloric acid
(5 mL of 5 M) was added to a stirred solution of compound
6a (0.60 g, 2.11 mmol) in 15 mL of acetonitrile at 0 ꢁC. The
mixture obtained was left for 2 h at 0 ꢁC. Then 20 mL of
water was added and the mixture was extracted with ethyl
acetate (3 · 15 mL). The organic layer was washed with
water (15 mL) and a saturated solution of NaHCO3
(2 · 10 mL) after which it was dried with anhydrous
MgSO4. The solvents were removed in vacuum and the resi-
due was purified by flash chromatography (hexane/ethyl
acetate, 4:1, Rf = 0.44) giving 0.37 g of resulting product
4.2. Synthesis of racemic fluoromevalonates
4.2.1. tert-Butyl (E)-5-ethoxy-3-hydroxy-3-(trifluoromethyl)-
4-pentenoate 6a. A 1.6 M solution of n-butyllithium in
hexane (0.81 mL) was added dropwise via syringe to a stir-
red solution of diisopropylamine (0.14 g, 1.4 mmol) in
5 mL of THF at ꢀ78 ꢁC under argon. After 15 min the
solution of tert-butyl acetate (0.20 g, 1.72 mmol) in 2 mL

1922
I. S. Kondratov et al. / Tetrahedron: Asymmetry 18 (2007) 1918–1925
1
as a colorless oil (56% yield). H NMR (CDCl3): dH 1.48 s
(9H, C(CH3)), 2.65 dd (1H, CHHCHO, JHH = 15.9,
2.6 Hz), 2.66 d (1H, CHHCO2Bu-t, JHH = 16.1 Hz), 2.71
d (1H, CHHCO2Bu-t, JHH = 16.1 Hz), 2.87 dd (1H,
CHHCHO, JHH = 15.9, 2.0 Hz), 5.67 s (1H, OH), 9.86 m
(1H, CH@O). 13C NMR (CDCl3): dC 27.9 (C(CH3)3),
37.5 (CH2CO2Bu-t), 46.7 (CH2CHO), 73.3 q (C(OH)CF3,
4.2.6. tert-Butyl 3-(difluoromethyl)-3,5-dihydroxypentanoate
8b. This was synthesized by a similar methodology as 8a
from compound 7b (0.2 g, 0.83 mmol) giving 0.15 g of
product 8b as a colorless oil (76% yield), Rf = 0.34 (hex-
1
ane/ethyl acetate, 4:1). H NMR (CDCl3): dH 1.47 s (9H,
C(CH3)), 1.76 ddd (1H, CHHCH2OH, JHH = 15.0, 5.9,
4.7 Hz), 1.96 ddd (1H, CHHCH2OH, JHH = 15.0, 6.3,
4.8 Hz), 2.56 d (1H, CHHCO2Bu-t, JHH = 16.5 Hz), 2.59
d (1H, CHHCO2tBu, JHH = 16.5 Hz), 2.99 br s (1H,
CH2OH), 3.84–3.92 m (2H, CH2OH), 5.18 s (1H,
CHF2COH), 5.77 t (1H, CHF2, JHF = 56.0 Hz). 13C
NMR (CDCl3): dC 27.9 (C(CH3)3), 35.9 (CH2CH2OH),
37.6 (CH2CO2Bu-t), 58.2 (CH2OH), 73.8 t (C–CHF2,
JCF = 29.5 Hz), 83.7 (C(CH3)3), 125.0 q (CF3, JCF
=
285.0 Hz), 170.5 (CO2t-Bu), 198.9 (CHO). 19F NMR
(CDCl3): dF ꢀ82.14 s (CF3). IR (CH2Cl2, cmꢀ1): m 3375,
3060, 2981, 1727, 1428, 1369, 1248, 1152, 1032. Anal. Calcd
for C10H15F3O4: C, 46.88; H, 5.90. Found: C, 46.69; H,
5.93.
JCF = 21.4 Hz), 82.6 (C(CH3)3), 116.7 t (CHF2, JCF
=
4.2.4. tert-Butyl 3-(difluoromethyl)-3-hydroxy-5-oxopenta-
noate 7b. This was synthesized by similar methodology as
7a from compound 6b (0.56 g, 2.11 mmol) giving 0.30 g of
product 7b as a colorless oil (61% yield), Rf = 0.34 (hexane/
ethyl acetate, 4:1). 1H NMR (CDCl3): dH 1.47 s (9H,
C(CH3)), 2.58 d (1H, CHHCO2Bu-t, JHH = 16.1 Hz),
2.65 d (1H, CHHCO2Bu-t, JHH = 16.1 Hz), 2.67 d (1H,
CHHCHO, JHH = 16.2 Hz), 2.79 d (1H, CHHCHO,
248.1 Hz), 171.6 (CO2Bu-t). 19F NMR (CDCl3): dF
ꢀ133.00 dd (1F, CHFF, JFF = 282.0, JHF = 56.0 Hz),
ꢀ131.66 dd (1F, CHFF, JFF = 282.0, JHF = 56.0 Hz). IR
(CH2Cl2, cmꢀ1): m 3673, 3606, 3448, 3060, 2981, 2936,
1702, 1480, 1426, 1367, 1244, 1155, 1077, 952. Anal. Calcd
for C10H18F2O4: C, 49.99; H, 7.55. Found: C, 49.87; H,
7.56.
JHH = 16.2 Hz), 4.86
s
(1H, OH), 5.82
t
(CHF2,
4.2.7. Tetrahydro-4-hydroxy-4-(trifluoromethyl)-2H-pyran-
2-one 3a. Trifluoroacetic acid (1 mL) was added to a solu-
tion of compound 8a (0.50 g, 1.94 mmol) in 10 mL of
CH2Cl2. The mixture was stirred at room temperature and
after 2 h the solvents were evaporated in vacuum and the
residue was purified by column chromatography (hexane/
ethyl acetate, 2:1, Rf = 0.28) giving 0.29 g of the resulting
JHF = 56.0 Hz), 9.84 s (1H, CH@O). 13C NMR: dC 27.9
(C(CH3)3), 38.1 t (CH2CO2Bu-t, JCF = 2.4 Hz), 46.7 t
(CH2CHO, JCF = 1.8 Hz), 72.7
t
(C–CHF2, JCF =
22.5 Hz), 83.0 (C(CH3)3), 115.9 t (CHF2, JCF = 249.0 Hz),
170.8 (CO2Bu-t), 199.8 (CHO). 19F NMR: dF ꢀ131.98 dd
(1F, CHFF, JFF = 284.3, JHF = 56.0 Hz), ꢀ130.94 dd
(1F, CHFF, JFF = 284.3, JHF = 56.0 Hz). IR (CH2Cl2,
cmꢀ1): m 3568, 3440, 3060, 2982, 2936, 1725, 1426, 1368,
1248, 1155, 1074, 975. Anal. Calcd for C10H16F2O4: C,
50.42; H, 6.77. Found: C, 50.58; H, 6.68.
1
product as a colorless oil (81% yield). H NMR (CDCl3):
dH 2.06 ddd (1H, CHHCH2O, JHH = 14.7, 4.2, 3.9 Hz),
2.20 ddd (1H, CHHCH2O, JHH = 14.7, 10.7, 5.1 Hz), 2.80
s (2H, CH2CO2), 4.15 br s (1H, OH), 4.44 ddd (1H, CHHO,
JHH = 11.5, 5.1, 4.2 Hz), 4.60 ddd (1H, CHHO, JHH = 11.5,
10.7, 3.9 Hz). 13C NMR (CDCl3): dC 28.5 (CH2CH2O), 36.8
(CH2CO2), 64.8 (CH2O), 71.3 q (C–CF3, JCF = 31.0 Hz),
124.8 q (CF3, JCF = 284 Hz), 168.9 (CO2). 19F NMR
(CDCl3): dF ꢀ84.84 s (CF3). IR (CH2Cl2, cmꢀ1): m 3672,
3564, 3400, 3060, 2984, 2928, 1750, 1480, 1402, 1304,
1228, 1184, 1016, 1000. Anal. Calcd for C6H7F3O3: C,
39.14; H, 3.83. Found: C, 39.01; H, 3.77.
4.2.5. tert-Butyl 3,5-dihydroxy-3-(trifluoromethyl)penta-
noate 8a. Acetic acid (0.44 g, 7.33 mmol) was added drop-
wise to stirring suspension of 0.09 g NaBH4 (2.37 mmol) in
5 mL of benzene under argon. The mixture was refluxed for
1 h and then cooled to 0 ꢁC. A solution of compound 7a
(0.24 g, 0.95 mmol) in 5 mL of benzene was added drop-
wise and the mixture obtained was stirred for 2 h at room
temperature. Then 5 mL of water was carefully added
dropwise. The organic layer was separated and water layer
was extracted with ether (3 · 10 mL). The combined organ-
ic layers were dried with anhydrous MgSO4, the solvents
were removed and the residue was purified by flash chro-
matography (hexane/ethyl acetate, 4:1, Rf = 0.27) giving
0.16 g of resulting product as a colorless oil (79% yield).
1H NMR (CDCl3): dH 1.48 s (9H, C(CH3)), 1.82 ddd
(1H, CHHCH2OH, JHH = 14.9, 6.3, 4.5 Hz), 2.12 ddd
(1H, CHHCH2OH, JHH = 14.9, 7.2, 4.2 Hz), 2.47 br s
(1H, CH2OH), 2.58 d (1H, CHHCO2Bu-t, JHH = 16.1 Hz),
2.75 d (1H, CHHCO2tBu, JHH = 16.1 Hz), 3.85–3.96 m
(2H, CH2OH), 5.80 s (1H, CF3COH). 13C NMR (CDCl3):
dC 27.9 (C(CH3)3), 35.6 (CH2CH2OH), 37.5 (CH2CO2Bu-
4.2.8. Tetrahydro-4-(difluoromethyl)-4-hydroxy-2H-pyran-
2-one 3b. This was synthesized by a similar methodology
as 3a from compound 8b (0.2 g, 0.84 mmol) giving 0.10 g
of the resulting product as a colorless oil (74% yield),
1
Rf = 0.54 (CH2Cl2/ethyl acetate, 2:1). H NMR (CDCl3):
dH 1.90 ddd (1H, CHHCH2O, JHH = 14.5, 4.5, 3.7 Hz),
2.09 ddd (1H, CHHCH2O, JHH = 14.5, 10.4, 5.1 Hz), 2.64
d (1H, CHHCO2, JHH = 17.5 Hz), 2.72 d (1H, CHHCO2,
JHH = 17.5 Hz), 4.00 br s (1H, OH), 4.38 ddd (1H, CHHO,
JHH = 11.5, 5.1, 4.5 Hz), 4.66 ddd (1H, CHHO, JHH = 11.5,
10.4, 3.7 Hz), 5.63 t (1H, CHF2, JHF = 56.0 Hz). 13C NMR
(CDCl3): dC 28.4 (CH2CH2O), 36.3 (CH2CO2), 65.1
(CH2O), 70.7 t (C–CHF2, JCF = 22.9 Hz), 115.9 t (CHF2,
JCF = 248.7 Hz), 170.3 (CO2). 19F NMR (CDCl3): dF
ꢀ133.82 dd (1F, CHFF, JFF = 284.4, JHF = 56.0 Hz),
ꢀ132.91 dd (1F, CHFF, JFF = 284.4, JHF = 56.0 Hz). IR
(CH2Cl2, cmꢀ1): m 3664, 3572, 3400, 3060, 2981, 2923,
1744, 1560, 1480, 1402, 1368, 1310, 1229, 1168, 11156,
1080, 1008, 981. Anal. Calcd for C6H8F2O3: C, 43.38; H,
4.85. Found: C, 43.30; H, 4.88.
t), 58.1 (CH2OH), 74.5
q (C–CF3, JCF = 28.5 Hz),
83.2 (C(CH3)3), 125.7 q (CF3, JCF = 286.1 Hz), 171.3
(CO2Bu-t). 19F NMR (CDCl3): dF ꢀ81.81 s (CF3). IR
(CH2Cl2, cmꢀ1): m 3614, 3384, 3060, 2978, 2940, 1705,
1456, 1428, 1372, 1320, 1248, 1184, 1078, 1040. Anal. Calcd
for C10H17F3O4: C, 46.51; H, 6.64. Found: C, 46.70; H,
6.60.

I. S. Kondratov et al. / Tetrahedron: Asymmetry 18 (2007) 1918–1925
1923
4.3. Preparation of optically active 6,6,6-tri- and 6,6-
difluoromevalonates
(CDCl3): dH 1.48 d (3H, CH3, JHH = 7.1 Hz), 1.72 dt
(1H, CHHCH2O, JHH = 15.3, 5.4 Hz), 1.91 dt (1H,
CHHCH2O, JHH = 15.3, 5.4 Hz), 2.42 d (1H, CHHC@O,
JHH = 15.1 Hz), 2.50 d (1H, CHHC@O, JHH = 15.1 Hz),
2.96 br s (1H, CH2IH), 3.84 t (2H, CH2IH, JHH = 5.4 Hz),
5.08 m (1H, CH3CH), 5.72 t (1H, CHF2, JHF = 55.6 Hz),
6.06 s (1H, IH), 6.51 d (1H, NH, JHH = 7.0 Hz), 7.25–
7.36 m (5H, Ph). 13C NMR (CDCl3): dC 21.5 (CH3), 35.6
(CH2), 37.8 (CH2), 49.1 (CH2IH), 58.3 (CH), 74.2 t (C–
CHF2, JCF = 20.3 Hz), 116.9 t (CHF2, JCF = 249.1 Hz),
126.1 (Ph), 127.6 (Ph), 128.8 (Ph), 142.5 (Ph), 170.6
(C@O). 19F NMR (CDCl3): dF ꢀ131.97 dd (1F, CHFF,
JFF = 240.8, JHF = 55.6 Hz), ꢀ131.27 dd (1F, CHFF,
JFF = 240.8, JHF = 55.6 Hz). IR (CH2Cl2, cmꢀ1): m 3427,
3338, 3060, 3033, 2974, 2933, 1649, 1524, 1496, 1449,
1376, 1224, 1067. Anal. Calcd for C14H19F2NO3: C,
58.53; H, 6.67; N, 4.88. Found: C, 58.67; H, 6.73; N, 4.81.
4.3.1. Typical procedure of the reaction of fluoromevalonates
3a and 3b with (S)-1-phenylethylamine and (1S)-1-(1-naph-
thyl)ethylamine. A solution of either compound 3a
(0.25 g, 1.36 mmol) or 3b (0.23 g, 1.36 mmol) and (1S)-1-
phenylethylamine (0.165 g, 1.36 mmol) in CH2Cl2 was kept
for 48 h at room temperature. The solvent was evaporated
in vacuum and diastereomeric amides (S)-10a,b and (R)-
10a,b were separated and purified by column chromatogra-
phy (for 10a: hexane/ethyl acetate, 2:1, for 10b: CH2Cl2/
ethyl acetate, 2:1). A similar procedure was used for the
preparation of analytical samples of (1S)-1-(1-naph-
thyl)ethylamides 11a and 11b, which was used for HPLC
control of the enantiomeric purity of fluoromevalonates
3a and 3b.
4.3.2. (3S)-3,5-Dihydroxy-N-[(1S)-1-phenylethyl]-3-(trifluoro-
methyl)pentanamide (S,S)-10a. The yield of the product
4.3.5. (3R)-3-(Difluoromethyl)-3,5-dihydroxy-N-((1S)-1-phen-
ylethyl)pentanamide (R,S)-10b. The yield of the product
was 0.11 g (27%) as a colorless oil, Rf = 0.39 (hexane/ethyl
was 0.08 g (21%) as a colorless oil. Rf = 0.42 (CH2Cl2/ethyl
25
acetate, 2:1), ½aꢁD ¼ ꢀ39:4 ðc 1:3; CHCl3Þ. 1H NMR
25
acetate, 2:1), ½aꢁD ¼ ꢀ45:5 ðc 0:7; CHCl3Þ. 1H NMR
(CDCl3): dH 1.52 d (3H, CH3, JHH = 6.9 Hz), 1.82 ddd
(1H, CHHCH2O, JHH = 15.0, 7.1, 3.8 Hz), 2.08 ddd (1H,
(CDCl3): dH 1.45 d (3H, CH3, JHH = 7.1 Hz), 1.72 dt
(1H, CHHCH2O, JHH = 14.6, 5.4 Hz), 1.88 dt (1H,
CHHCH2O, JHH = 14.6, 5.8 Hz), 2.45 d (1H, CHHC@O,
JHH = 15.1 Hz), 2.50 d (1H, CHHC@O, JHH = 15.1 Hz),
3.46 br s (1H, CH2IH), 3.80 m (2H, CH2IH), 5.05 m
(1H, CH3CH), 5.66 t (1H, CHF2, JHF = 55.9 Hz), 6.00 s
(1H, IH), 7.03 d (1H, NH, JHH = 7.9 Hz), 7.20–7.36 m
(5H, Ph). 13C NMR (CDCl3): dC 21.7 (CH3), 35.2 (CH2),
38.1 (CH2), 49.0 (CH2IH), 58.2 (CH), 74.2 t (C–CHF2,
JCF = 21.5 Hz), 116.7 t (CF3, JCF = 249.3 Hz), 126.1
(Ph), 127.5 (Ph), 128.7 (Ph), 142.7 (Ph), 170.6 (C@O). 19F
NMR (CDCl3): dF ꢀ131.73 d (CHF2, JHF = 55.9 Hz). IR
(CH2Cl2, cmꢀ1): m 3427, 3060, 3032, 2971, 2932, 1651,
1525, 1496, 1450, 1376, 1232, 1066. Anal. Calcd for
C14H19F2NO3: C, 58.53; H, 6.67; N, 4.88. Found: C,
58.61; H, 6.66; N, 4.79.
CHHCH2O, JHH = 15.0, 7.1, 3.9 Hz), 2.43
d (1H,
CHHC@O, JHH = 15.0 Hz), 2.47 m (1H, CH2IH), 2.68 d
(1H, CHHC@O, JHH = 15.0 Hz), 3.90 m (2H, CH2IH),
5.13 m (1H, CH3CH), 6.16 d (1H, NH, JHH = 6.4 Hz),
6.66 s (1H, IH), 7.28–7.40 m (5H, Ph). 13C NMR (CDCl3):
dC 21.4 (CH3), 35.4 (CH2), 38.0 (CH2), 49.2 (CH2IH), 58.2
(CH), 75.1 q (C–CF3, JCF = 28.1 Hz), 125.8 q (CF3,
JCF = 288.0 Hz), 126.2 (Ph), 127.7 (Ph), 128.8 (Ph), 142.3
(Ph), 170.0 (C@O). 19F NMR (CDCl3): dF ꢀ82.23 s
(CF3). IR (CH2Cl2, cmꢀ1): m 3425, 3304, 3060, 2975,
2321, 1653, 1524, 1496, 1451, 1374, 1323, 1240, 1175,
1136, 1075, 1018, 916. Anal. Calcd for C14H18F3NO3: C,
55.08; H, 5.94; N, 4.59. Found: C, 55.34; H, 5.89; N, 4.45.
4.3.3. (3R)-3,5-Dihydroxy-N-[(1S)-1-phenylethyl]-3-(trifluoro-
methyl)pentanamide (R,S)-10a. The yield of the product
4.3.6. Typical procedure of hydrolysis optically pure (S)-(ꢀ)-
1-phenylethylamides 10a and 10b. A mixture of 5 mL of
4 M hydrochloric acid and the corresponding amide (10a:
0.10 g, 0.33 mmol, 10b: 0.10 g, 0.35 mmol) in 5 mL of ace-
tonitrile was refluxed for 30 min, cooled to room tempera-
ture, extracted with diethyl ether (3 · 10 mL) and the
combined organic layers were dried over MgSO4. The sol-
vents were removed in vacuum and the residue was purified
by column chromatography (3a: hexane/ethyl acetate, 2:1,
Rf = 0.28, 3b: hexane/ethyl acetate, 4:1, Rf = 0.34).
was 0.10 g (24%) as a colorless oil, Rf = 0.33 (hexane/ethyl
25
acetate, 2:1), ½aꢁD ¼ ꢀ54:0 ðc 0:6; CHCl3Þ. 1H NMR
(CDCl3): dH 1.51 d (3H, CH3, JHH = 7.0 Hz), 1.77–1.86
m (1H, CHHCH2O), 2.05 ddd (1H, CHHCH2O, JHH
=
14.9, 6.5, 3.4 Hz), 2.48 d (1H, CHHC@O, JHH = 15.0 Hz),
2.67 d (1H, CHHC@O, JHH = 15.0 Hz), 2.47 br s (1H,
CH2IH), 3.89 m (2H, CH2IH), 5.13 m (1H, CH3CH),
6.35 d (1H, NH, JHH = 6.1 Hz), 6.52 br s (1H, IH), 7.27–
7.40 m (5H, Ph). 13C NMR (CDCl3): dC 21.5 (CH3), 35.5
(CH2), 38.5 (CH2), 49.1 (CH2IH), 58.4 (CH), 75.1 q (C–
CF3, JCF = 27.7 Hz), 125.7 q (CF3, JCF = 286.2 Hz),
126.1 (Ph), 127.6 (Ph), 128.7 (Ph), 142.4 (Ph), 169.7
(C@O). 19F NMR (CDCl3): dF ꢀ82.17 s (CF3). IR
(CH2Cl2, cmꢀ1): m 3424, 3320, 3060, 2976, 2336, 1654,
1525, 1496, 1448, 1375, 1177, 1136, 1077, 1024, 922. Anal.
Calcd for C14H18F3NO3: C, 55.08; H, 5.94; N, 4.59. Found:
C, 55.37; H, 5.90; N, 4.49.
4.3.7.
(4S)-4-Hydroxy-4-(trifluoromethyl)tetrahydro-2H-
pyran-2-one (S)-3a. This was obtained from (S,S)-10a.
Crystallized from a mixture of diethyl ether/hexane. The
yield of the product is 0.045 g (75%). White needles.
25
½aꢁD ¼ 18:7 ðc 1; CHCl3Þ. Mp 62–64 ꢁC. For spectral data
see Section 4.2.7.
4.3.4. (3S)-3-(Difluoromethyl)-3,5-dihydroxy-N-((1S)-1-phen-
ylethyl)pentanamide (S,S)-10b. The yield of the product
4.3.8.
(4R)-4-Hydroxy-4-(trifluoromethyl)tetrahydro-2H-
pyran-2-one (R)-3a. This was obtained from (R,S)-10a.
Crystallized from a mixture of diethyl ether/hexane. The
yield of the product is 0.04 g (65%). White needles.
was 0.11 g (29%) as a colorless oil. Rf = 0.45 (CH2Cl2/ethyl
25
acetate, 2:1), ½aꢁD ¼ ꢀ33:2 ðc 0:7; CHCl3Þ. 1H NMR

1924
25
I. S. Kondratov et al. / Tetrahedron: Asymmetry 18 (2007) 1918–1925
½aꢁD ¼ ꢀ17:0 ðc 0:8; CHCl3Þ. Mp 63–65 ꢁC. For spectral
C6H6F3NaO4Æ0.5H2O: C, 31.18, H, 3.05. Found: C,
31.25; H, 3.00.
data see Section 4.2.7.
4.3.9. (4S)-4-Tetrahydro-4-(difluoromethyl)-4-hydroxy-2H-
pyran-2-one (S)-3b. This was obtained from (S,S)-10b.
4.4.3. 6,6-Difluoromevaldate 12b. This was synthesized by
a similar methodology to 12a from compound 7b (0.5 g,
2.10 mmol) and 0.28 g of the resulting product 12b was
obtained as a colorless powder by crystallization from benz-
ene (73% yield). Mp 84–86 ꢁC. IR (KBr, cmꢀ1): m 3448,
2992, 2940, 1684, 1416, 1386, 1368, 1288, 1266, 1208,
1176, 1131, 1082, 1048, 1016, 963, 904. Anal. Calcd for
C6H8F2O4: C, 39.57; H, 4.43. Found: C, 39.68; H, 4.48.
NMR-spectra contain signals of lactols 12-Ib and 12-IIb
and acyclic form 13b (the percentage of 13b is near 30–
40% in various solvents such as D2O, DMSO-d6, acetone-
d6, etc.).
The yield of the product was 0.041 g (71%). Colorless oil.
25
½aꢁD ¼ þ12:2 ðc 0:8; CHCl3Þ. For spectral data see Section
4.2.8.
4.3.10. (4R)-4-Tetrahydro-4-(difluoromethyl)-4-hydroxy-2H-
pyran-2-one (R)-3b. This was obtained from (R,S)-10b.
The yield of the product is 0.035 g (65%). Colorless oil.
25
½aꢁD ¼ ꢀ10:5 ðc 0:7; CHCl3Þ. For spectral data see Section
4.2.8.
4.4. Preparation of 6,6,6-trifluoromevaldate 12a and 6,6-
difluoromevaldates 12b
4.4.3.1. 4-(Difluoromethyl)-4,6-dihydroxytetrahydro-2H-
pyran-2-ones 12-Ib and 12-IIb. 1H NMR (DMSO-d6): dH
4.4.1. 6,6,6-Trifluoromevaldate 12a. Trifluoroacetic acid
(1 mL) was added to a solution of compound 7a (0.50 g,
2.07 mmol) in 10 mL of CH2Cl2. The mixture was stirred
at room temperature and after 2 h, the solvents were evap-
orated in vacuum and the residue purified by crystallization
from benzene to give 0.30 g of the resulting product as a
colorless powder (77% yield). Mp 123–124 ꢁC. IR (KBr,
cmꢀ1): m 3429, 2992, 2944, 1684, 1472, 1448, 1384, 1337,
1308, 1257, 1209, 1176, 1120, 1048, 992, 964. Anal. Calcd
for C6H7F3O4: C, 36.01; H, 3.53. Found: C, 36.14; H,
3.59. NMR-spectra contain signals of lactols 12-Ia and
12-IIa and acyclic form 13a (the percentage of 13a is near
30–40% in various solvents such as D2O, DMSO-d6, ace-
tone-d6, etc.).
1.68–1.83 m (1H, CHHCHO2), 1.95–2.08 m (1H,
CHHCHO2), 2.34–2.80 m (2H, CH2CO2), 5.47–6.20 m
(3H, OH, CHF2, CH2CHO2), 7.70 br s (1H, OH); 19F
NMR (DMSO-d6): dF ꢀ132.91 dd (minor epimer, 1F,
CHFF, JFF = 279.0, JHF = 57.3 Hz), ꢀ133.86 dd (minor
epimer, 1F, CHFF, JFF = 279.0, JHF = 57.3 Hz), ꢀ134.06
dd (major epimer, 1F, CHFF, JFF = 281.4, JHF = 57.3 Hz),
ꢀ134.72 dd (major epimer, 1F, CHFF, JFF = 281.4,
JHF = 57.3 Hz).
4.4.3.2. 3-(Difluoromethyl)-3-hydroxy-5-oxopentanoic acid
13b. 1H NMR (DMSO-d6): 2.41–2.80 m (4H, CH2CHI
and CH2CI2H), 5.71–6.00 m (2H, CHF2, OH), 9.73 s
(1H, CHO). 19F NMR (DMSO-d6): dF ꢀ132.40 dd (1F,
CHFF, JFF = 278.3, JHF = 56.0 Hz), ꢀ132.40 dd (1F,
CHFF, JFF = 278.3, JHF = 56.0 Hz).
4.4.1.1. 4,6-Dihydroxy-4-(trifluoromethyl)tetrahydro-2H-
pyran-2-ones 12-Ia and 12-IIa. 1H NMR (DMSO-d6): dH
1.84–1.93
m
(1H, CHHCHO2), 2.14–2.38
m
(1H,
4.4.4. Sodium 3-(difluoromethyl)-3-hydroxy-5-oxopentano-
ate 14b. This was synthesized by a similar methodology
as 14a from compound 12b (0.18 g, 1.00 mmol) and
0.13 g of the resulting product 14b was obtained as a color-
less hydroscopic solid (64% yield). IR (KBr, cmꢀ1): m 3440,
CHHCHO2), 2.75–3.03 m (2H, CH2CO2), 5.58–5.71 m
(1H, CH2CHO), 6.69 br s (1H, OH), 7.76 br s (1H, IH);
19F NMR (DMSO-d6): dF ꢀ83.81 s (minor epimer CF3),
ꢀ83.72 s (major epimer CF3).
1
1720, 1592, 1405, 1295, 1064. H NMR (DMSO-d6): dH
4.4.1.2. 3-Hydroxy-5-oxo-3-(trifluoromethyl)pentanoic acid
13a. 1H NMR (DMSO-d6): 2.54–3.04 m (4H, CH2CHI
and CH2CI2H), 6.70 br s (1H, OH), 9.73 s (1H, CHO).
19F NMR (DMSO-d6): dF ꢀ81.73 s (CF3).
2.21–2.23 m (2H, CH2CI2), 2.39 d (1H, CHHCHO,
JHH = 14.5 Hz), 2.49 d (1H, CHHCHO, JHH = 14.5. Hz),
5.81 t (1H, CHF2, JHF = 56.0 Hz), 9.72 s (1H, CHO). 13C
NMR (DMSO-d6): dC 39.6 (CH2), 48.1 (CH2), 72.4 t (C–
CHF2, JCF = 20.9 Hz), 117.8 t (CHF2, JCF = 247.5 Hz),
174.2 (CI2), 198.3 (CHI). 19F NMR (DMSO-d6): dF
ꢀ129.27 dd (1F, CHFF, JFF = 278.3, JHF = 56.0 Hz),
ꢀ132.18 dd (1F, CHFF, JFF = 278.3, JHF = 56.0 Hz).
Anal. Calcd for C6H7F2NaO4Æ0.5H2O: C, 33.82; H, 3.78.
Found: C, 33.70; H 3.85.
4.4.2. Sodium 3-hydroxy-5-oxo-3-(trifluoromethyl)pentano-
ate 14a. A solution of 0.03 g (0.75 mmol) of NaOH in
2 mL of water was added to a solution of 12a (0.2 g,
1.00 mmol) in 5 mL of water. After 15 min, a water solu-
tion was extracted with ethyl acetate (3 · 5 mL) to extract
the excess of trifluoromevaldate. The water layer was evap-
orated and the residue was dried in vacuum giving 0.14 g of
the resulting product 14a as a colorless hydroscopic solid
(61% yield). IR (KBr, cmꢀ1): m 3472, 1723, 1591, 1401,
1288, 1176. 1H NMR (DMSO-d6): dH 2.22 s (2H, CH2CI2),
2.48 m (1 H, CHHCHO), 2.55 dd (1H, CHHCHO,
JHH = 15.0, 2.9 Hz), 9.70 m (1H, CH@O), 10.93 br s
(1H, IH). 13C NMR (DMSO-d6): dC 38.2 (CH2), 49.1
(CH2), 72.4 q (C–CF3, JCF = 27.6 Hz), 126.9 q (CF3,
JCF = 287.5 Hz), 173.0 (CI2), 198.1 (CHI). 19F NMR
Acknowledgments
The work was supported by fellowship from National
Scholarship Program of World Federation of Scientists
ICSC ‘World Laboratory’ (Mr. Ivan S. Kondratov). We
thank Enamine Ltd. (Kiev) for technical and financial sup-
port, also we appreciate Mrs. S. V. Shishkina and Dr. O. V.
Shishkin (STC ‘Institute for Single Crystals’, Kharkov) for
the performing of the X-ray diffraction study.
(DMSO-d6): dF ꢀ81.24
s (CF3). Anal. Calcd for

I. S. Kondratov et al. / Tetrahedron: Asymmetry 18 (2007) 1918–1925
1925
10. (a) Knauss, H. J.; Brodie, J. D.; Porter, J. W. J. Lipid Res.
1962, 3, 197–206; (b) Retey, J.; von Stetten, E.; Coy, U.;
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Rees, H. H.; Goodwin, T. W. Biochem. J. 1974, 139, 205–209.
11. (a) Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo,
S. Chem. Lett. 1976, 499–502; (b) Hojo, M.; Masuda, R.;
Sakaguchi, S.; Takagawa, H. Synthesis 1986, 1016–1017; (c)
Gerus, I. I.; Gorbunova, M. G.; Kukhar, V. P. J. Fluorine
Chem. 1994, 69, 195–198; (d) Nenajdenko, V. G.; Sanin, A.
V.; Balenkova, E. S. Russ. Chem. Rev. 1999, 68, 483–505; (e)
Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G.
Tetrahedron 2007, 63, 7753–7808.
12. (a) Gerus, I. I.; Tolmacheva, N. A.; Vdovenko, S. I.;
Fro¨hlich, R.; Haufe, G. Synthesis 2005, 1269–1278; (b)
Tolmachova, N. A.; Gerus, I. I.; Vdovenko, S. I.; Essers,
M.; Fro¨hlich, R.; Haufe, G. Eur. J. Org. Chem. 2006, 4704–
4709; (c) Shaitanova, E. N.; Gerus, I. I.; Belik, M. Yu.;
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Kondratov, I. S.; Gerus, I. I.; Furmanova, M. V.; Vdovenko,
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