Stereoselective synthesis of both enantiomers of trifluoro-γ-valerolactone and pentafluoro-γ-caprolactone

Article abstract of DOI:10.1002/1099-0690(200206)2002:12<1895::AID-EJOC1895>3.0.CO;2-1

Both enantiomers of 5-(trifluoromethyl)dihydrofuran-2-one (1a) and 5-(pentafluoroethyl)dihydrofuran-2-one (1b) have been synthesised stereoselectively, in four steps, starting from chiral (R)- or (S)-3-[(4-methylphenyl)sulfinyl]propionic acid (2) and comm

Full text of DOI:10.1002/1099-0690(200206)2002:12<1895::AID-EJOC1895>3.0.CO;2-1

FULL PAPER
Stereoselective Synthesis of Both Enantiomers of Trifluoro-γ-valerolactone and
Pentafluoro-γ-caprolactone
Pierfrancesco Bravo,[a] Massimo Frigerio,[a] Alfonso Melloni,[a] Walter Panzeri,[b]
Cristina Pesenti,[a] Fiorenza Viani,*[b] and Matteo Zanda[a]
Keywords: Fluorine / Lactones / Sulfoxides / Pheromones / Asymmetric synthesis
Both enantiomers of 5-(trifluoromethyl)dihydrofuran-2-one
(1a) and 5-(pentafluoroethyl)dihydrofuran-2-one (1b) have
been synthesised stereoselectively, in four steps, starting
from chiral (R)- or (S)-3-[(4-methylphenyl)sulfinyl]propionic
acid (2) and commercially available perfluorinated esters.
Compound (+)-(S)-1b is the pentafluoro analogue of the
aggregation pheromone of Trogoderma glabrum.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
The quasi-isosteric substitution of a fluorine atom for hy-
drogen in insect pheromones can alter the perception of the
natural substrate by competitive binding of the fluorinated
analogue with specific pheromone receptors, giving rise to
disruption of the mating communication system.[1] This
could represent an environmentally friendly, highly selective
strategy for insect pest control,[2] and a clever alternative
to insecticides, whose use is generally affected by serious
ecological drawbacks.
The γ-lactone nucleus is a rather common substructure
in pheromones. In this context, we have described a stereo-
selective synthesis of enantiomerically pure β-fluoroalkyl-γ-
lactones,[3] based on a novel application of Marino’s sulfox-
ide-directed lactonization.[4] Recently, we became interested
in enantiomerically pure γ-fluoroalkyl-γ-lactones, such as
1a and 1b (Figure 1). The latter is a pentafluoro analogue
of (ϩ)-(R)-γ-caprolactone, a pheromone of several Dermes-
tidae beetles.[5] In spite of their simple molecular structure,
to the best of our knowledge only a couple of syntheses of
enantiopure γ-perfluoroalkyl-γ-lactones have been de-
scribed in the literature, in both cases concerning the tri-
fluoromethyl (Tfm) derivative 1a.[6,7] In this paper we pre-
sent a stereoselective entry to 5-Tfm-dihydrofuran-2-one
(R)-1a, 5-C2F5-dihydrofuran-2-one (S)-1b, and their enanti-
omers.
Figure 1. Enantiomerically pure 5-Tfm and 5-C2F5 γ-lactones
The strategy for the preparation of 1 (Scheme 1) is based
on the assembly of enantiopure (R)- or (S)-3-(p-tolylsulfin-
yl)propionic acid (2) with commercially available perfluor-
inated acetic (RF ϭ CF3) or propionic (RF ϭ C2F5) esters.[8]
The stereogenic steps of the synthesis are: (1) the C-fluoro-
acylation of the C,O-dilithium derivative of 2, and (2) the
crucial carbonyl reduction of the intermediate β-ketosulfox-
ides to install the carbinolic stereocentre of the sulfinyl alco-
hols 3.[9] Deoxygenation of the sulfinyl group to give 6, fol-
lowed by lactonization to 7, and final reductive desulfenyl-
ation lead to the final targets 1.
[a]
Dipartimento di Chimica del Politecnico,
Via Mancinelli 7, 20131 Milano, Italy
[b]
C.N.R. Istituto di Chimica del Riconoscimento Molecolare
(ICRM),
Via Mancinelli 7, 20131 Milano, Italy
Fax: (internat.) ϩ39-(0)2/2399-3080
E-mail: viani@dept.chem.polimi.it
Supporting information for this article is available on the
WWW under http://www.eurjoc.com or from the author.
Scheme 1. Retrosynthetic analysis
Eur. J. Org. Chem. 2002, 1895Ϫ1902  WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0612Ϫ1895 $ 20.00ϩ.50/0
1895

P. Bravo, M. Frigerio, A. Melloni, W. Panzeri, C. Pesenti, F. Viani, M. Zanda
FULL PAPER
and 3d,e/3f ϭ 14.4:1.0.[14] The predominant diastereomers
3a and 3d were isolated by flash chromatography (FC) in 62
and 75% yields, and constituted 77 and 84%, respectively, of
Results and Discussion
Synthesis of the β-Sulfinyl-γ-hydroxy Acids 3
the whole mixtures of products, showing that the overall
facial diastereocontrol was also very good.
The dilithium derivatives of enantiomerically pure (R)-
or (S)-3-(sulfinyl)propionic acids 2 were condensed on ethyl
trifluoroacetate (Scheme 2) and ethyl pentafluoropropion-
ate (Scheme 3), respectively. Both reactions proceeded
smoothly, although the intermediate 3-sulfinyl-4-oxo-4-
fluoroalkylcarboxylic acids gave partial elimination of p-
TolSOH during the workup, producing the α,β-unsaturated
acids 4a,b as by-products.
A reasonable stereochemical outcome of the reaction is
as follows. Fluoroacylation is probably a nonstereoselective
process (Scheme 4), as already observed for analogous reac-
tions,[9,13] affording a nearly equimolar mixture of two in-
termediate β-keto-sulfoxides epimers at C(3) in equilibrium
with their gem-diol forms. Under the basic reduction condi-
tions (NaBH4, THF/H2O) a stereoconvergent dynamic
kinetic resolution should take place, whereby the oxo-form
of the (3S)-diastereomer is reduced at a higher rate than
the (3R)-diastereomer, which in turn is epimerised at C(3),
regenerating the (3S)-substrate.[15]
Scheme 2. Key: i) 1. LDA (2.0 equiv.), THF, Ϫ60 °C; 2. CF3CO2Et,
THF, Ϫ70 °C; 3. 1  HCl (pH 2); ii) 1. NaBH4, THF/H2O, 0 °C;
2. 1  HCl (pH 2)
Scheme 4. Stereoselective formation of 3a by NaBH4 reduction
with dynamic kinetic resolution
The good diastereocontrol in favour of 3a may be due to
the fact that hydride delivery takes place intramolecularly by
action of an intermediate acyloxy borohydride (Scheme 5),
Scheme 3. Key: i) 1. LDA (2.0 equiv.), THF, Ϫ 60 °C; 2. which might be the actual reducing species, through the
FelkinϪAhn model TS-1.[16] An analogous stereochemical
C2F5CO2Et, THF, Ϫ 70 °C; 3. 1  HCl (pH 2); ii) 1. NaBH4, THF/
H2O, 0 °C; 2. 1  HCl (pH 2)
outcome can be envisaged for the formation of the C2F5
derivative 3d, through a quasi-enantiomeric model.
The crude products were rapidly treated with NaBH4 to
give the γ-fluoroalkyl-γ-hydroxy-β-sulfinylcarboxylic acids
3,[10,11] which proved to be sufficiently stable to allow puri-
fication by flash chromatography (FC) and spectroscopic
characterisation.[12]
The two series of sulfinyl carbinols 3aϪc (Tfm derivat-
ives) and 3dϪf (C2F5 derivatives), having opposite config-
urations due to the use of the enantiomeric starting mat-
erials (R)- and (S)-2, were produced with analogous stereo-
chemical outcome and very good stereocontrol, which was
Scheme 5. Model for the stereoselective NaBH4 reduction
Surprisingly, the lactonisation process did not take place
totally unexpected on the basis of both our previous experi- spontaneously for 3a and 3d. In fact, at the end of the puri-
ence and literature reports on poorly stereoselective reduc- fication by FC on silica gel, only small amounts of trans
tions of similar substrates by action of borohydrides.[9,13] sulfinyl lactones 5c and 5f (Figure 2) arising from the minor
In this case, three of the four possible diastereomers were 3c and 3f syn precursors were detected. The cis sulfinyl lac-
obtained in very good overall yields, with a remarkable 3,4- tones arising from the main diastereomeric anti alcohols
anti-simple diastereoselectivity, in ratios 3a,b/3c ϭ 8.4:1.0 3a,d were never detected. This is probably a result of the
1896
Eur. J. Org. Chem. 2002, 1895Ϫ1902

Fluorinated Pheromone Analogues
FULL PAPER
steric strain induced by the bulky Tfm and C2F5 groups, 5 min),[22] affording the lactone (4S,5S)-7a in similar yield
which affects the cis-lactone isomers, making their forma- (70%), without any detectable epimerisation.
tion from anti-3a,b and 3d,e more difficult.
Hydrogenolytic Removal of the p-Tolylthio Group
The final step was the reductive removal of the p-tolylthio
group, which was performed by Raney-Ni hydrogenolysis in
ethylene glycol at reflux temperature under H2 atmosphere.
Starting from the cis lactones 7a and 7d, the enantiopure
desulfinylated γ-Tfm-γ-valerolactone (Ϫ)-(R)-1a and γ-pen-
tafluoroethyl-γ-caprolactone (ϩ)-(S)-1b were obtained
Figure 2. Spontaneously formed trans-sulfinyllactones
(Scheme 6). The same reaction, performed on the corres-
ponding trans lactones 7c and 7f led to the enantiomers
(ϩ)-(S)-1a and (Ϫ)-(R)-1b, respectively. The use of ethanol
as solvent was less effective, affording significant amounts
(ca. 20%) of ethyl 5,5,5-trifluoro-4-hydroxypentanoate or
ethyl 5,5,6,6,6-pentafluoro-4-hydroxyhexanoate from 7a
and 7d, respectively, by competitive solvolysis of the lac-
tones 1a and 1b, probably due to the presence of the elec-
tron-withdrawing Tfm and C2F5 groups on C-4, which
make the carboxy group strongly electrophilic.[23]
Completion of the Synthesis of 1a,b
The thermal lability of the sulfinyl derivatives 3 led us to
perform the next steps of the synthesis on their stable sul-
fenyl derivatives. The DrabowiczϪOae procedure[17] (tri-
fluoroacetic anhydride, NaI) allowed us to obtain the anti
4-hydroxy-3-sulfenyl acids (3S,4S)-6a [Equation (1) in
Scheme 6] and (3R,4R)-6d [Equation (2) in Scheme 6] from
the corresponding major trifluoro and pentafluoro diastere-
omers 3a and 3d. Not surprisingly, very little of the spon-
taneous cis lactonization products (4S,5S)-7a and (4R,5R)-
7d was detected after workup (4 and 1.2% isolated yields,
respectively).
Concluding Remarks
A synthesis of both enantiomers of the trifluoro analogue
of γ-valerolactone (1a) and the pentafluoro analogue of γ-
caprolactone (1b) has been developed using sulfoxide chem-
istry. The key installation of the C(4) stereogenic centres,
which was achieved by NaBH4 reduction of β-keto-sulfox-
ide precursors, occurred with unexpectedly high stereocon-
trol, probably originating from an intramolecular hydride
delivery by a transient carboxy-borohydride. A concomitant
dynamic kinetic resolution ensured a very effective synthesis
of the intermediate β-hydroxy sulfoxides 3a and 3d, which
were converted into the title compounds in three further
steps.
Scheme 6. Key: i) NaI, (CF3CO)2O, acetone, Ϫ 40 °C; ii)
CH3CO2H, toluene, reflux, 4 h; iii) DCC, DMAP, CH2Cl2, 0 °C;
iv) Raney Ni, H2, (CH2OH)2, ∆, 2 h
Experimental Section
General Details: Melting points (m.p.): uncorrected; capillary ap-
paratus. Polarimetric analyses: PROPOL polarimeter. Analytical
TLC: routinely used to monitor reactions, plates precoated with
Merck silica gel 60 F254 of 0.25 mm thickness were used. Flash
chromatography (FC): silica gel 60 (230Ϫ400 ASTM mesh). 1H
and 19F NMR: Bruker AC 250 L (250 MHz) (19F and 13C), Bruker
ARX400 (400 MHz) (1H), chemical shifts in ppm (δ), tetramethyl-
silane (TMS) as internal standard for 1H and 13C nuclei (δH ϭ 0.00
ppm), C6F6 external standard (δF ϭ Ϫ162.90 ppm) for 19F, coup-
ling constants are expressed in Hz. MS: TSQ Finnigan Mat three-
stage quadrupole instrument, DIS (Direct Inlet System) used for
pure compounds. GC/MS: TSQ Finnigan Mat having a transfer
line with Varian 3400 GC instrument. GC: DB-5 fused silica capil-
laries column [5% phenyl, 95% methyl silicone; 30 m ϫ 0.25 mm;
␾ ϭ 0.25 µm; carrier gas: He, 12 mL/min; temperature gradient
operating: 40 °C (1 min) Ǟ 200 °C (1 min); 10 °C/min Ǟ 285
(24 min)]. IR: PerkinϪElmer System 2000 FT-IR (scan range:
15600 cmϪ1; combined scan direction). THF was freshly distilled
from Na/benzophenone, diisopropylamine was freshly distilled
On the other hand, the same reaction performed on mix-
tures of anti/syn (3R/S,4R,RS)-3b,c (1.2:1.0) and (3S/
R,4S,SS)-3e,f (1.5:1.0) led to enantio- and diastereopure
trans-lactonisation products derived only from the syn alco-
hols 3c and 3f.[18] Since the diastereoisomers 3b,c and 3e,f
are rather difficult to separate from each other by FC, this
finding provided us with a straightforward entry to their
stereochemically pure derivatives.
Since the lactonisation of the major anti-sulfenyl derivat-
ives 6a,d did not take place spontaneously,[19] a way to per-
form this step was studied next. Among the different
methods of lactonization of γ-hydroxycarboxylic acids de-
scribed in the literature,[6a,6c,7,20] we chose the treatment
with acetic acid in toluene, which required heating of the
mixture for 4 h at reflux temperature.[21] The cis-lactones
were obtained in good yields (73.2 and 71.4% for 7a and
7d, respectively). Even more conveniently, the Tfm substrate
6a was treated with DCC (CH2Cl2, 0 °C, cat. DMAP, from CaH2; in all other cases, commercially available reagent-grade
Eur. J. Org. Chem. 2002, 1895Ϫ1902 1897

P. Bravo, M. Frigerio, A. Melloni, W. Panzeri, C. Pesenti, F. Viani, M. Zanda
FULL PAPER
solvents were employed without purification. All reactions, where 7.7 and 8.1 (m, 4 H, ArH) ppm. 19F NMR (CD3COCD3): δ ϭ
3
anhydrous organic solvents were employed, were performed under
nitrogen, after flame-drying of the glass apparatus. Synthesis of
(R)-3-(tolylsulfinyl)propionic acid (2) has already been described in
detail[8b] and the synthesis of its (S)-2 enantiomer was performed
following the same procedure, starting from (Ϫ)-(S)-methyl p-to-
lyl sulfoxide.
Ϫ74.3 (d, JF-H ϭ 7.6 Hz) ppm.
1
(3S,4R,RS)-3c: H NMR (CD3OD): δ ϭ 2.41 (s, 3 H, CH3), 2.71
2
3
2
3
(dd, J ϭ 18.2, J ϭ 6.6 Hz, 1 H, 2-Ha), 2.83 (dd, J ϭ 18.2, J ϭ
5.0 Hz, 1 H, 2-Hb), 3.65 (ddd, 3J ϭ 6.6, 5.0, 2.5 Hz, 1 H, 3-H),
3
4.43 (qd, JH-F ϭ 7.5, 3J ϭ 2.5 Hz, 1 H, 4-H), 7.3 and 7.6 (m, 4 H,
ArH) ppm. 19F NMR (CD3OD): δ ϭ Ϫ76.0 (d, JF-H ϭ 7.6 Hz)
3
1
ppm. H NMR (CD3COCD3): δ ϭ 2.87 (s, 3 H, CH3), 3.22 (ddq,
Synthesis of β-Sulfinyl-γ-hydroxy Acids 3. General Procedure: A so-
lution of 3-sulfinylpropionic acid (2) (10.0 mmol) in THF (30 mL)
was added dropwise at Ϫ 60 °C to a solution of LDA (24.0 mmol)
under argon atmosphere. The resulting yellow solution was cooled
to Ϫ70 °C and added with neat fluorinated esters (CF3CO2Et or
CF3CF2CO2Et) (14.0 mmol). After 5 min, a saturated NH4Cl solu-
tion was added, followed by a dilute HCl solution (until pH ϭ 2).
The mixture was extracted with EtOAc (3 ϫ 50 mL), washed with
water, dried over anhydrous sodium sulfate, filtered and concen-
trated in vacuo at room temp. The residue was diluted with a H2O/
THF (1:4) solution (30 mL), the mixture was cooled to 0 °C and
neat NaBH4 (40.0 mmol) was added portionwise. The resulting
clear solution was treated with 1  HCl aqueous solution until pH
2, the organic layers were extracted with EtOAc (3 ϫ 50 mL),
washed with water, dried over anhydrous sodium sulfate, filtered
and the solvents evaporated to dryness at room temp. under va-
cuum.
2J ϭ 18.9, 3J ϭ 6.0, JH-F ϭ 0.5 Hz, 1 H, 2-Ha), 3.31 (dd, 2J ϭ
5
3
3
18.9, J ϭ 5.1 Hz, 1 H, 2-Hb), 4.11 (ddd, J ϭ 6.0, 5.1, 2.7 Hz, 1
H, 3-H), 5.14 (qd, 3J ϭ 8.0, 3JH-F ϭ 2.7 Hz, 1 H, 4-H), 7.7 and 8.2
(m, 4 H, ArH) ppm. 19F NMR (CD3COCD3): δ ϭ Ϫ75.6 (d,
3JF-H ϭ 8.0 Hz) ppm.
5,5,5-Trifluoro-4-hydroxy-2-pentenoic Acid [(R/S,E)-4a]: 1H NMR
(CD3OD): δ ϭ 4.68 (qdd, 3JH-F ϭ 7.2, J ϭ 5.0, 4J ϭ 1.9 Hz, 1 H,
3
3
4
3
4-H), 6.26 (dd, J ϭ 15.7, J ϭ 1.9 Hz, 1 H, 2-H), 6.85 (dd, J ϭ
15.7, J ϭ 5.0 Hz, 1 H, 3-H) ppm. 13C NMR (CD3OD): δ ϭ 73.2
4
(q, J ϭ 30.9 Hz, C-4), 129.0 (q, J ϭ 282.6 Hz, C-5), 139.2 (s, C-2),
143.7 (s, C-3), 176.0 (s, C-1) ppm. 19F NMR (CD3OD): δ ϭ Ϫ77.4
3
(d, JF-H ϭ 7.2 Hz) ppm.
4-(Tolylsulfinyl)-5-trifluoromethyldihydrofuran-2-one [(4S,5R,RS)-
5c]: Yield 292 mg (10%), formed during the FC (CHCl3/EtOAc/
AcOH, 70:30:1); Rf ϭ 0.50. [α]2D0 ϭ ϩ159.5 (c ϭ 0.4, CHCl3); m.p.
95Ϫ97 °C (from diisopropyl ether). 1H NMR (CDCl3): δ ϭ 2.44
(s, 3 H, CH3), 2.49 (dd, J ϭ 18.6, J ϭ 9.8 Hz, 1 H, 3-Ha), 3.03
(dd, J ϭ 18.6, J ϭ 5.7 Hz, 1 H, 3-Hb), 3.61 (ddd, J ϭ 9.8, 5.7,
From (RS)-2 and CF3CO2Et: (3S,4S,RS)-3a/(3R,4R,RS)-3b/
2
3
1
(3S,4R,RS)-3c ϭ 7.2:1.2:1.0 (measured by H and 19F NMR spec-
2
3
3
troscopy in CDCl3, CD3COCD3, and CD3OD); 80.4% overall
yield. The 4-hydroxyalkenoic acid (R/S,E)-4a was formed in vari-
able amounts depending on the degree of elimination of p-TolSOH
from 3aϪc.
3
3
4.6 Hz, 1 H, 4-H), 5.07 (qd, JH-F ϭ 6.0, J ϭ 4.6 Hz, 1 H, 5-H),
7.25 and 7.40 (m, 4 H, ArH) ppm. 19F NMR (CDCl3): δ ϭ Ϫ79.1
3
(d, JF-H ϭ 6.0 Hz) ppm.
From (S)-2 and CF3CF2CO2Et: (3R,4R,SS)-3d/(3S,4S,SS)-3e/
(3R,4S,SS)-3f ϭ 12.9:1.5:1.0 (determined by 1H and 19F NMR
spectroscopy of the crude reaction mixture in CD3OD); 89.5%
global yields. The 4-hydroxyalkenoic acid (R/S,E)-4b was detected
in a variable amount depending on the degree of elimination of
p-TolSOH from 3dϪf.
5,5,5-Trifluoro-4-hydroxy-3-(tolylsulfinyl)pentanoic Acid
[(3S,4S,RS)-3a]: Yield 1.91 g (61.6%) obtained after FC (CHCl3/
EtOAc/AcOH, 70:30:1); Rf ϭ 0.35. [α]2D0 ϭ ϩ143 (c ϭ1.1, CD3OD).
2
1H NMR (CD3OD): δ ϭ 2.41 (s, 3 H, CH3), 2.58 (dd, J ϭ 17.6,
2
3
3J ϭ 7.2 Hz, 1 H, 2-Ha), 2.76 (dd, J ϭ 17.6, J ϭ 4.4 Hz, 1 H, 2-
3
3
Hb), 3.44 (ddd, J ϭ 7.2, 4.4, 8.3 Hz, 1 H, 3-H), 4.44 (qd, JH-F
ϭ
8.4, J ϭ 8.3 Hz, 1 H, 4-H), 7.3 and 7.6 (m, 4 H, ArH) ppm. 19F
3
5,5,6,6,6-Pentafluoro-4-hydroxy-3-(tolylsulfinyl)hexanoic Acid
[(3R,4R,SS)-3d]: Yield 2.7 g (75.0%), obtained after FC (CHCl3/
EtOAc/AcOH, 40:60:1.5); Rf ϭ 0.35. [α]2D0 ϭ Ϫ137 (c ϭ 0.3,
CD3OD). IR (neat): ν˜ ϭ 3306 cmϪ1, 1732, 1702, 1421, 1214, 1210,
NMR (CD3OD): δ ϭ Ϫ74.8 (d, JF-H ϭ 8.4 Hz) ppm. 1H NMR
3
2
3
(CD3COCD3): δ ϭ 2.86 (s, 3 H, CH3), 3.08 (dd, J ϭ 18.6, J ϭ
6.6 Hz, 1 H, 2-Ha), 3.28 (ddq, 2J ϭ 18.6, 3J ϭ 4.5, 5JH-F ϭ 1.0 Hz,
1 H, 2-Hb), 3.90 (m, 1 H, 3-H), 5.08 (m, 1 H, 4-H), 7.8 and 8.0 (m,
4 H, ArH) ppm. 13C NMR (CD3OD): δ ϭ 21.3 (s, CH3), 27.6 (s,
C-2), 63.1 (s, C-3), 70.7 (q, J ϭ 31.7 Hz, C-4), 128.3 (q, J ϭ
282.6 Hz, C-5), 128.2 (s, ArCCH3), 128.7 (s, ArC), 133.4 (s, ArCS),
133.7 (s, ArC), 177.8 (s, C-1) ppm. 19F (CD3OD): δ ϭ Ϫ74.4 (d,
3JF-H ϭ 7.8 Hz) ppm. IR (neat): ν˜ ϭ 3210 cmϪ1, 2956, 2395, 1724,
1687, 1416, 1243. MS (DIS EI, 70 eV): m/z (%) ϭ 310 (8) [Mϩ·],
292 (3) [C12H11SO3F3ϩ·], 139 (28) [C7H7SO؉], 101 (17) [C4H5O3ϩ],
91 (37) [C4H5F2ϩ], 77 (42) [C6H5ϩ], 69 (100) [CF3ϩ].
1
1126, 1035. H NMR (CD3OD): δ ϭ 2.40 (s, 3 H, CH3), 2.63 (dd,
2J ϭ 18.2, 3J ϭ 7.0 Hz, 1 H, 2-Ha), 2.82 (ddd, 2J ϭ 18.2, 3J ϭ 4.5,
3
4J ϭ 1.4 Hz, 1 H, 2-Hb), 3.54 (ddd, J ϭ 7.0, 4.5, 5.5 Hz, 1 H, 3-
3
3
H), 4.59 (ddd, JH-F ϭ 21.5, 4.3, J ϭ 5.5 Hz, 1 H, 4-H), 7.1 and
7.5 (m, 4 H, ArH) ppm. 13C NMR (CD3OD): δ ϭ 21.4 (s, CH3),
27.6 (s, C-2), 63.05 (s, C-3), 69.4 (dd, J ϭ 31.4, 20.3 Hz, C-4), 116.0
(tq, J ϭ 257.1, 35.2 Hz, C-5), 120.5 (qt, J ϭ 292.2, 35.2 Hz, C-6),
125.4 (s, ArC), 126.3 (s, ArCCH3), 130.9 (s, ArCS), 131.3 (s, ArC),
173.5 (s, C-1) ppm. 19F NMR (CD3OD): δ ϭ Ϫ80.3 (s, 3 F, CF3),
2
3
Ϫ116.8 (dd, JF-F ϭ 275.9, JF-H ϭ 4.3 Hz, 1 F, CFa), Ϫ127.4 (dd,
(3R/S,4R,RS)-3b,c: Yield 580 mg (18.7%) obtained as a 1.2:1.0 mix-
ture by FC (CHCl3/EtOAc/AcOH, 70:30:1); Rf ϭ 0.35.
2JF-F ϭ 275.9, JF-H ϭ 21.5 Hz, 1 F, CFb) ppm. MS (DIS EI,
3
70 eV): m/z (%) ϭ 361 (5) [M ϩ H]ϩ, 360 (8) [Mϩ·], 342 (5)
[C13H11SO3F5ϩ·], 140 (25) [C7H8SO؉·], 139 (100) [C7H7SO؉], 101
(42) [C4H5O3ϩ], 69 (8) [CF3ϩ].
2
(3R,4R,RS)-3b: 1H NMR (CD3OD): δ ϭ 2.19 (dd, J ϭ 17.6, 3J ϭ
2
3
7.2 Hz, 1 H, 2-Ha), 2.41 (s, 3 H, CH3), 2.91 (ddq, J ϭ 17.6, J ϭ
4.4, 5JH-F ϭ 1.2 Hz, 1 H, 2-Hb), 3.85 (ddd, 3J ϭ 7.2, 7.2, 4.4 Hz, 1
(3S/R,4S,SS)-3e,f: Yield 522 mg (14.5%) obtained as a 1.5:1.0 mix-
ture by FC (CHCl3/EtOAc/AcOH, 70:30:1); Rf ϭ 0.35.
H, 3-H), 3.94 (qd, 3JH-F ϭ 6.9, 3J ϭ 7.2 Hz, 1 H, 4-H), 7.3 and 7.7
(m, 4 H, ArH) ppm. 19F NMR (CD3OD): δ ϭ Ϫ74.7 (d, JF-H
ϭ
3
6.9 Hz) ppm. 1H NMR (CD3COCD3): δ ϭ 2.73 (dd, 2J ϭ 18.0, (3S,4S,SS)-3e: 1H NMR (CD3OD): δ ϭ 2.25 (ddd, 2J ϭ 19.2, 3J ϭ
2
4
2
3J ϭ 7.5 Hz, 1 H, 2-Ha), 2.86 (s, 3 H, CH3), 3.48 (ddq, J ϭ 18.0,
7.5, J ϭ 1.3 Hz, 1 H, 2-Ha), 2.40 (s, 3 H, CH3), 2.89 (ddd, J ϭ
5
3
4
3
3J ϭ 4.5, JH-F ϭ 1.2 Hz, 1 H, 2-Hb), 4.28 (ddd, 3J ϭ 8.4, 7.5, 19.2, J ϭ 4.7, J ϭ 2.3 Hz, 1 H, 2-Hb), 3.91 (ddd, J ϭ 7.5, 4.7,
4.5 Hz, 1 H, 3-H), 4.62 (qd, J ϭ 8.4, JH-F ϭ 7.6 Hz, 1 H, 4-H), 4.4 Hz, 1 H, 3-H), 4.23 (dddd, JH-F ϭ 22.0, J ϭ 4.4, 2.3, 1.3 Hz,
1898 Eur. J. Org. Chem. 2002, 1895Ϫ1902
3
3
3
3

Fluorinated Pheromone Analogues
FULL PAPER
3
5
2
1 H, 4-H), 7.1 and 7.5 (m, 4 H, ArH) ppm. 19F NMR (CD3OD):
2J ϭ 16.8, J ϭ 11.4, JH-F ϭ 1.2 Hz, 1 H, 3-Hβ), 2.86 (ddq, J ϭ
2
5
δ ϭ Ϫ80.4 (s, 3F, CF3), Ϫ122.7 (d, JF-F ϭ 275.9 Hz, 1 F, CFa),
16.8, 3J ϭ 8.8, JH-F ϭ 1.2 Hz, 1 H, 3-Hα), 4.16 (m, 1 H, 4-H),
2
3
3
3
Ϫ129.3 (dd, JF-F ϭ 275.9, JF-H ϭ 22.0 Hz, 1 F, CFb) ppm.
4.87 (dq, JH-F ϭ 7.6, J ϭ 7.6 Hz, 1 H, 5-H), 7.10 and 7.45 (m, 4
H, ArH) ppm. 13C NMR (CDCl3): δ ϭ 21.1 (s, CH3), 34.1 (s, C-
3), 43.4 (s, C-4), 77.0 (q, J ϭ 32.0 Hz, C-5), 123.1 (q, J ϭ 283.1 Hz,
CF3), 128.8 (s, ArCCH3), 130.4 (s, ArC), 132.9 (s, ArC), 139.1 (s,
ArCS), 171.9 (s, C-2) ppm. 19F NMR (CDCl3): δ ϭ Ϫ73.4 (d,
3JF-H ϭ 7.6 Hz) ppm. IR (neat): ν˜ ϭ 1709 cmϪ1, 1212, 1210, 1120,
1006. MS (DIS EI 70 eV): m/z (%) ϭ 276 (100) [Mϩ·], 150 (15)
[C9H10S؉·], 135 (16) [C5H5F2O2ϩ], 123 (11) [C7H7Sϩ].
(3R,4S,SS)-3f: 1H NMR (CD3OD): δ ϭ 2.40 (s, 3 H, CH3), 2.74
(ddd, 2J ϭ 19.5, 3J ϭ 10.0, 4J ϭ 0.9 Hz, 1 H, 2-Ha), 2.99 (ddd,
3
4
2J ϭ 19.5, J ϭ 4.5, J ϭ 0.5 Hz, 1 H, 2-Hb), 3.77 (m, 1 H, 3-H),
4.20 (m, 1 H, 4-H), 7.1 and 7.5 (m, 4 H, ArH) ppm. 19F NMR
2
(CD3OD): δ ϭ Ϫ80.5 (s, 3 F, CF3), Ϫ116.8 (dd, JF-F ϭ 275.8,
3JF-H ϭ 5.6 Hz, 1 F, CFa), Ϫ127.2 (dd, JF-F ϭ 275.8, JF-H
ϭ
2
3
19.8 Hz, 1 F, CFb) ppm.
(4S,5R)-7c: Yield 80% from a (3R/S,4R,RS)-3b,c mixture with
1.2:1.0 ratio, after FC (CHCl3/EtOAc/AcOH, 90:10:1); Rf ϭ 0.60.
5,5,6,6,6-Pentafluoro-4-hydroxy-2-hexenoic Acid [(R/S,E)-4b]: 1H
NMR (CD3OD): δ ϭ 4.80 (m, 1 H, 4-H), 6.25 (dd, 3J ϭ 13.7, 4J ϭ
1.2 Hz, 1 H, 2-H), 6.85 (dd, 3J ϭ 13.7, 4J ϭ 5.2 Hz, 1 H, 3-H)
ppm. 13C NMR (CD3OD): δ ϭ 69.7 (dd, J ϭ 55.6, 25.9 Hz, C-4),
115.0 (tq, J ϭ 257.1, 35.2 Hz, C-5), 120.2 (qt, J ϭ 292.2, 35.2 Hz,
C-6), 136.7 (s, C-2), 139.7 (s, C-3), 168.7 (s, C-1) ppm. 19F NMR
1
[α]2D0 ϭ Ϫ55.5 (c ϭ 0.15, CHCl3). H NMR (CDCl3): δ ϭ 2.35 (s,
3 H, CH3), 2.57 (ddd, J ϭ 18.6, 3J ϭ 3.1, 5JH-F ϭ 1.0 Hz, 1 H, 3-
2
2
3
3
Hβ), 3.04 (dd, J ϭ 18.6, J ϭ 8.3 Hz, 1 H, 3-Hα), 3.96 (ddd, J ϭ
3
3
8.3, 3.1, 2.5 Hz, 1 H, 4-H), 4.63 (qd, JH-F ϭ 6.3, J ϭ 2.5 Hz, 1
H, 5-H), 7.15 and 7.40 (m, 4 H, ArH) ppm. 13C NMR (CDCl3):
δ ϭ 21.2 (s, CH3), 30.9 (s, C-3), 41.3 (s, C-4), 79.8 (q, J ϭ 32.9 Hz,
C-5), 122.8 (q, J ϭ 282.3 Hz, CF3), 126.7 (s, ArCCH3), 130.9 (s,
ArC), 134.2 (s, ArC), 140.0 (s, ArCS), 170.8 (s, C-2) ppm. 19F
2
(CD3OD): δ ϭ Ϫ79.9 (s, 3 F, CF3), Ϫ120.0 (dd, JF-F ϭ 275.9,
3JF-H ϭ 7.3 Hz, 1 F, CFa), Ϫ127.3 (dd, JF-F ϭ 275.9, JF-H
ϭ
2
3
15.9 Hz, 1 F, CFb) ppm.
3
NMR (CDCl3): δ ϭ Ϫ79.5 (d, JF-H ϭ 6.3 Hz) ppm. MS (DIS EI,
5-Pentafluoroethyl-4-(tolylsulfinyl)dihydrofuran-2-one [(4R,5S,SS)-
5f]: Yield 171 mg (5%), formed during the FC (CHCl3/EtOAc/
AcOH, 70:30:1); Rf ϭ 0.45. [α]2D0 ϭ Ϫ169 (c ϭ 0.2, CHCl3); m.p.
105Ϫ106 °C (from diisopropyl ether). 1H NMR (CDCl3): δ ϭ 2.46
70 eV): m/z (%) ϭ 276 (100) [Mϩ·], 150 (18) [C9H10S؉·], 135 (40)
[C5H5F2O2ϩ], 123 (36) [C7H7Sϩ], 91 (33) [C4H5F2ϩ], 77 (16)
[C6H5ϩ], 69 (9) [CF3ϩ].
2
4
(s, 3 H, CH3), 2.48 (ddd, J ϭ 18.6, 3J ϭ 9.8, J ϭ 4.6 Hz, 1 H, 3-
5,5,6,6,6-Pentafluoro-4-hydroxy-3-(p-tolylthio)hexanoic
Acid
2
3
3
Ha), 3.08 (dd, J ϭ 18.6, J ϭ 6.2 Hz, 1 H, 3-Hb), 3.74 (ddd, J ϭ (3R,4R)-6d: Yield 82.7% from (3R,4R,SS)-3d, isolated after FC
9.8, 6.2, 6.3 Hz, 1 H, 4-H), 5.20 (dddd, 3JH-F ϭ 19.1, 1.6, 3J ϭ 6.3,
(CHCl3/EtOAc/AcOH, 90:10:1); Rf ϭ 0.35. [α]2D0 ϭ Ϫ5.9 (c ϭ 1.9,
4J ϭ 4.6 Hz, 1 H, 5-H), 7.25 and 7.40 (m, 4 H, ArH) ppm. 19F CHCl3). [α] ϭ Ϫ23.5 (c ϭ 1.9, CHCl3); m.p. 105Ϫ107 °C (from
20
365
2
NMR (CDCl3): δ ϭ Ϫ83.3 (s, 3 F, CF3), Ϫ125.8 (d, JF-F
ϭ
diisopropyl ether). 1H NMR (CDCl3): δ ϭ 2.33 (s, 3 H, CH3), 2.77
2
3
2
3
2
3
281.0 Hz, 1 F, CFa), Ϫ132.0 (dd, JF-F ϭ 281.0, JF-H ϭ 19.1 Hz, (dd, J ϭ 17.2, J ϭ 7.9 Hz, 1 H, 2-Ha), 2.94 (dd, J ϭ 17.2, J ϭ
1 F, CFb) ppm.
6.5 Hz, 1 H, 2-Hb), 3.45 (br. s, 1 H, OH), 3.77 (m, 1 H, 3-H), 4.12
3
3
(ddd, JH-F ϭ 20.0, 3.6, J ϭ 5.6 Hz, 1 H, 4-H), 7.10 and 7.45 (m,
4 H, ArH), 10.2 (br. s, 1 H, COOH) ppm. 13C NMR (CDCl3): δ ϭ
21.1 (s, CH3), 37.5 (s, C-2), 46.9 (s, C-3), 69.4 (dd, J ϭ 28.5,
21.7 Hz, C-4), 113.7 (tq, J ϭ 263.4, 36.54 Hz, C-5), 118.7 (qt, J ϭ
286.7, 34.1 Hz, C-6), 127.6 (s, ArCCH3), 130.2 (s, ArC), 134.3 (s,
ArC), 139.4 (s, ArCS), 176.4 (s, C-1) ppm. 19F NMR (CDCl3): δ ϭ
Sulfur Deoxygenation of β-Sulfinyl-γ-hydroxy Acids (3). General
Procedure: A solution of trifluoroacetic anhydride (25.0 mmol) in
acetone (20 mL) was added dropwise to a suspension of NaI
(15.0 mmol) and 3 (5.0 mmol) in acetone (20 mL) cooled to Ϫ40
°C and stirred under argon atmosphere. A mixture of saturated
aqueous solutions of Na2SO3 and NaHCO3 was added dropwise
to the resulting dark green slurry, the pH was adjusted to 2 by
adding a 1  HCl aqueous solution, the organic layers were ex-
tracted with EtOAc (3 ϫ 25 mL), dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo.
2
3
Ϫ83.3 (s, 3 F, CF3), Ϫ120.0 (dd, JF-F ϭ 274.7, JF-H ϭ 3.6 Hz, 1
2
3
F, CFa), Ϫ132.0 (dd, JF-F ϭ 274.7, JF-H ϭ 20.0 Hz, 1 F, CFb)
ppm. MS (DIS EI, 70 eV): m/z (%) ϭ 344 (100) [Mϩ·], 326 (27)
[C13H11SO2F5ϩ·], 267 (9) [C11H8SF5ϩ], 196 (6) [C10H12SO2ϩ·], 195
(36) [C10H11SO2ϩ], 177 (56) [C10H9SO؉], 161 (10) [C4H2OF5ϩ], 149
(37) [C9H9S؉], 123 (82) [C7H7Sϩ], 91 (72) [C4H5F2ϩ], 77 (56)
[C6H5ϩ], 69 (22) [CF3ϩ].
5,5,5-Trifluoro-4-hydroxy-3-(p-tolylthio)pentanoic Acid [(3S,4S)-6a]:
Yield 82.7% from (3S,4S,RS)-3a, isolated after FC (CHCl3/EtOAc/
AcOH, 90:10:1); Rf ϭ 0.35. [α]2D0 ϭ ϩ5.5 (c ϭ 0.5, CHCl3); m.p.
80Ϫ82 °C (from diisopropyl ether). 1H NMR (CDCl3): δ ϭ 2.36
5-Pentafluoroethyl-4-(p-tolylthio)dihydrofuran-2-one
(4R,5R)-7d:
Yield 1.2% from 6d; Rf ϭ 0.40. [α]2D0 ϭ Ϫ39.5 (c ϭ 0.45, CHCl3).
2
3
1H NMR (CDCl3): δ ϭ 2.36 (s, 3 H, CH3), 2.76 (ddd, J ϭ 17.0,
2
(s, 3 H, CH3), 2.74 (dd, J ϭ 15.4, J ϭ 7.7 Hz, 1 H, 2-Ha), 2.90
(dd, 2J ϭ 15.4, 3J ϭ 5.4 Hz, 1 H, 2-Hb), 3.50 (br. s, 1 H, OH),
3.64Ϫ3.71 (m, 1 H, 3-H), 4.01Ϫ4.09 (m, 1 H, 4-H), 7.1 and 7.5 (m,
4 H, ArH) ppm. 13C NMR (CDCl3): δ ϭ 21.1 (s, CH3), 37.1 (s, C-
2), 46.8 (s, C-3), 71.0 (q, J ϭ 30.6 Hz, C-4), 124.5 (q, J ϭ 283.3 Hz,
C-5), 128.7 (s, ArCCH3), 130.1 (s, ArC), 134.2 (s, ArC), 139.4 (s,
ArCS), 176.0 (s, C-1) ppm. 19F NMR (CDCl3): δ ϭ Ϫ76.01 (d,
3JH-F ϭ 7.0 Hz) ppm. IR (neat): ν˜ ϭ 3025 cmϪ1, 2926, 1714, 1412,
1269, 1171, 1137. MS (DIS EI, 70 eV): m/z (%) ϭ 294 (100) [Mϩ·],
276 (13) [C11H11SO2F3ϩ·], 196 (3) [C10H12SO2ϩ·], 195 (23)
[C10H11SO2ϩ], 177 (21) [C10H9SO؉], 153 (13) [C5H7O3F2ϩ], 149
(10) [C9H9S؉], 123 (16) [C7H7Sϩ].
4
2
3
3J ϭ 9.1, J ϭ 2.7 Hz, 1 H, 3-Hβ), 2.86 (ddd, J ϭ 17.0, J ϭ 8.3,
4J ϭ 2.0 Hz, 1 H, 3-Hα), 4.19 (m, 1 H, 4-H), 4.95 (dddd, JH-F
ϭ
3
3
4
23.5, J ϭ 7.2, J ϭ 2.7, 2.0 Hz, 1 H, 5-H), 7.1 and 7.4 (m, 4 H,
ArH) ppm. 13C NMR (CDCl3), δ ϭ 21.1 ppm (s, CH3), 34.9 (s, C-
3), 44.6 (s, C-4), 75.4 (dd, J ϭ 32.1, 22.1 Hz, C-5), 113.2 (tq, J ϭ
264.0, 37.4 Hz, CF2), 118.2 (qdd, J ϭ 286.0, 35.7, 33.0 Hz, CF3),
128.9 (s, ArCCH3), 130.2 (s, ArC), 133.2 (s, ArC), 139.2 (s, ArCS),
171.6 (s, C-2) ppm. 19F NMR (CDCl3): δ ϭ Ϫ82.7 (s, 3 F, CF3),
Ϫ118.9 (d, 2JF-F ϭ 280.9 Hz, 1 F, CFa), Ϫ130.5 (dd, 2JF-F ϭ 280.9,
3JF-H ϭ 23.5 Hz, 1 F, CFb) ppm. MS (DIS EI, 70 eV): m/z (%) ϭ
327 (18) [M ϩ H]ϩ, 326 (100) [Mϩ·], 161 (5) [C4H2OF5ϩ], 150 (42)
[C9H10S؉·], 149 (37) [C9H9S؉], 135 (65) [C5H5O2F2ϩ], 123 (42)
[C7H7Sϩ], 91 (26) [C4H5F2ϩ], 77 (18) [C6H5ϩ].
4-p-Tolylthio-5-trifluoromethyldihydrofuran-2-one
[(4S,5S)-7a]:
Yield 4%, spontaneously formed from 6a and isolated after FC
(CHCl3/EtOAc/AcOH, 90:10:1); Rf ϭ 0.40. [α]2D0 ϭ ϩ32 (c ϭ 0.25,
(4R,5S)-7f: Yield 95% from (3R,4S,SS)-3f, isolated after FC (n-hex-
CHCl3). 1H NMR (CDCl3): δ ϭ 2.35 (s, 3 H, CH3), 2.73 (ddq, ane/diisopropyl ether, 4:1); Rf ϭ 0.35. [α]2D0 ϭ ϩ50.5 (c ϭ 1.2,
Eur. J. Org. Chem. 2002, 1895Ϫ1902
1899

P. Bravo, M. Frigerio, A. Melloni, W. Panzeri, C. Pesenti, F. Viani, M. Zanda
FULL PAPER
CHCl3). 1H NMR (CDCl3): δ ϭ 2.38 (s, 3 H, CH3), 2.59 (ddd,
(S)-1a: Yield 55% from (4S,5R)-7c (Method B, n-pentane/ethyl
2J ϭ 18.6, J ϭ 2.6, JH-F ϭ 1.5 Hz, 1 H, 3-Hβ), 3.04 (dddd, J ϭ ether, 4:1); Rf ϭ 0.35 (n-pentane/ethyl ether, 3:2). [α]2D0 ϭ ϩ14 (c ϭ
3
5
2
3
5
3
18.6, J ϭ 8.7, JH-F ϭ 1.3, 0.5 Hz, 1 H, 3-Hα), 4.07 (dddt, J ϭ 1.2, CHCl3). All the spectroscopic data matched those described
4
3
8.7, 3.1, 2.6, JH-F ϭ 1.04 Hz, 1 H, 4-H), 4.73 (ddd, JH-F ϭ 18.9,
above for the enantiomer.
4.0, J ϭ 2.6 Hz, 1 H, 5-H), 7.1 and 7.4 (m, 4 H, ArH) ppm. 13C
3
Ethyl 5,5,5-Trifluoro-4-hydroxypentanoate: Yield 20% when using
EtOH as solvent with 7a, by prolonging the reaction time to 3 h;
Rf ϭ 0.30 (n-pentane/ethyl ether, 3:2). 1H NMR (CDCl3): δ ϭ 1.21
(t, 3J ϭ 6.8 Hz, 3 H, CH3), 1.80Ϫ2.10 (m, 4 H, 2-H2 ϩ 3-H2), 3.70
NMR (CDCl3): δ ϭ 21.2 (s, CH3), 33.9 (s, C-3), 40.9 (s, C-4), 78.8
(dd, J ϭ 32.1, 22.1 Hz, C-5), 116.0 (tq, J ϭ 260.0, 37.6 Hz, CF2),
121.0 (qdd, J ϭ 286.0, 36.0, 32.0 Hz, CF3), 126.7 (s, ArCCH3),
130.6 (s, ArC), 134.4 (s, ArC), 140.1 (s, ArCS), 172.3 (s, C-2) ppm.
3
(br. s, 1 H, OH), 3.90Ϫ4.05 (m, 1 H, 4-H), 4.13 (q, J ϭ 6.8 Hz, 2
19F NMR (CDCl3): δ ϭ Ϫ83.3 (s, 3 F, CF3), Ϫ125.9 (dd, JF-F
ϭ
2
H, OCH2) ppm. 13C NMR (CDCl3): δ ϭ 14.2 (s, CH3), 24.9 (s, C-
3), 29.7 (s, C-2), 60.9 (s, OCH2), 69.5 (q, J ϭ 31.3 Hz, C-4), 125.2
(q, J ϭ 281.9 Hz, CF3), 173.6 (s, C-1) ppm. 19F NMR (CDCl3):
3
2
280.0, JF-H ϭ 4.0 Hz, 1 F, CFa), Ϫ132.45 (dd, JF-F ϭ 280.0,
3JF-H ϭ 18.9 Hz, 1 F, CFb) ppm. MS (DIS EI, 70 eV): m/z (%) ϭ
327 (8) [M ϩ H]ϩ, 326 (100) [(M)ϩ·], 286 (7) [C11H11SOF5ϩ·], 161
(8) [C4H2OF5ϩ], 150 (39) [C9H10S؉·], 149 (41) [C9H9S؉], 135 (58)
[C5H5O2F2ϩ], 123 (38) [C7H7Sϩ].
3
δ ϭ Ϫ81.3 (d, JF-H ϭ 6.2 Hz) ppm. MS (DIS EI, 70 eV):
m/z (%)
ϭ
200 (3) [Mϩ·], 182 (9) [C7H9O2F3ϩ·], 155 (6)
[C5H6O2F3ϩ], 85 (100) [C4H5O2ϩ], 69 (17) [CF3ϩ].
Synthesis of β-Sulfenyl-γ-lactones (7). General Procedure, Method
A: A solution of sulfenylhydroxy acid 6 (1.0 mmol) and acetic acid
(40 mmol) in toluene (20 mL) was refluxed for 24 h under N2 atmo-
sphere. Then the cooled solution was washed with a 5% aq
NaHCO3 solution (2 ϫ 5 mL), water (2 ϫ 5 mL), dried over anhyd-
rous sodium sulfate, filtered and the solvents evaporated to dryness
under reduced pressure. The residue was crystallised from diisopro-
pyl ether providing the corresponding lactone 7.
5-Pentafluoroethyldihydrofuran-2-one (S)-1b: Yield 62% from
(4R,5R)-7d (Method B, n-pentane/ethyl ether, 3:2); Rf ϭ 0.35.
[α]2D0 ϭ ϩ22.5 (c ϭ 0.8, CHCl3). 1H NMR (CDCl3): δ ϭ 2.44Ϫ2.78
(m, 4 H, 3-H2 ϩ 4-H2), 4.80Ϫ4.96 (m, 1 H, 5-H) ppm. 13C NMR
(CDCl3): δ ϭ 20.7 (s, C-4), 26.2 (s, C-3), 74.3 (dd, J ϭ 33.0,
23.2 Hz, C-5), 112.3 (tq, J ϭ 259.0, 37.1 Hz, CF2), 118.7 (qt, J ϭ
284.9, 35.9 Hz, CF3), 174.5 (s, C-2) ppm. 19F NMR (CDCl3): δ ϭ
2
3
Ϫ83.7 (s, 3 F, CF3), Ϫ125.0 (dd, JF-F ϭ 279.6, JF-H ϭ 4.5 Hz, 1
2
3
F, CFa), Ϫ132.3 (dd, JF-F ϭ 279.6, JF-H ϭ 18.5 Hz, 1 F, CFa)
ppm. MS (GC EI 70 eV): m/z (%) ϭ 205 (100) [M ϩ H]ϩ, 177 (6)
[C5H6OF5ϩ·], 109 (16) [C3H3O2F2ϩ]. GC/MS; t1, m/z (%) ϭ
5.51 min, 204 (98) [Mϩ].
(4S,5S)-7a: Yield 73.2% from (3S,4S)-6a, isolated after FC (cyclo-
hexane/diisopropyl ether, 3:2); Rf ϭ 0.35. All the physical and spec-
troscopic data matched those described above.
(4R,5R)-7d: Yield 71.4% from (3R,4R)-6d, isolated after FC (cyclo-
hexane/diisopropyl ether, 3:2); Rf ϭ 0.35. All the physical and spec-
troscopic data matched those described above.
(R)-1b: Yield 66% from (4R,5S)-7f (Method B, n-pentane/ethyl
ether, 3:2); Rf ϭ 0.35. [α]2D0 ϭ Ϫ23.5 (c ϭ 1.1, CHCl3). All the
spectroscopic data matched those of the above described enanti-
omer.
Method B: Neat DCC (1.1 mmol) was added to a stirred solution
of (3S,4S)-6a (1.0 mmol) in CH2Cl2 (10 mL) cooled to 0 °C. Stir-
ring was continued for 5 min, then neat DMAP (0.1 mmol) was
added. A white solid precipitated immediately and was filtered off.
The clear solution was concentrated to dryness.
Ethyl 5,5,6,6,6-Pentafluoro-4-hydroxyhexanoate: Yield 20% when
using EtOH as solvent with 7d, by prolonging the reaction time to
3 h; Rf ϭ 0.30 (n-pentane/ethyl ether, 3:2). 1H NMR (CDCl3): δ ϭ
1.26 (t, 3J ϭ 8.8 Hz, 3 H, CH3), 1.90Ϫ2.15 (m, 2 H, 3-H2),
3
(4S,5S)-7a: Yield: 70% after FC (cyclohexane/diisopropyl ether
1:1). [α]2D0 ϭ ϩ29 (c ϭ 0.25, CHCl3). All the physical and spectro-
scopic data matched those described above.
2.45Ϫ2.65 (m, 2 H, 2-H2), 4.05Ϫ4.20 (m, 1 H, 4-H), 4.17 (q, J ϭ
8.8 Hz, 2 H, OCH2) ppm. 13C NMR (CDCl3): δ ϭ 14.1 (s, CH3),
24.1 (s, C-3), 29.7 (s, C-2), 60.9 (s, OCH2), 69.4 (dd, J ϭ 27.3,
23.3 Hz, C-4), 113.6 (tq, J ϭ 257.0, 35.9 Hz, C-5), 119.2 (qt, J ϭ
284.5, 35.9 Hz, C-6), 173.9 (s, C-1) ppm. 19F NMR (CDCl3): δ ϭ
Synthesis of Butanolides 1. General Procedure: A black slurry of
sulfenyl lactone 7 (1.0 mmol) and Raney-Ni (threefold excess by
weight) in ethylene glycol (6 mL) was stirred under H2 atmosphere
at reflux for 2 h. After the starting compound was totally used up,
the black powder was let to decant, the clear solution was poured
into a vessel, water added and the organic products extracted with
diethyl ether (3 ϫ 5 mL). The combined ether solutions were then
dried over anhydrous sodium sulfate, filtered and carefully concen-
trated at room temperature by blowing a gentle N2 flow over the
solution. The residue was purified by two alternative methods: (A)
fractional distillation at atmospheric pressure, or (B) flash chroma-
tography.
2
3
Ϫ82.8 (s, 3 F, CF3), Ϫ127.5 (dd, JF-F ϭ 279.5, JF-H ϭ 4.5 Hz, 1
2
3
F, CFa), Ϫ133.8 (dd, JF-F ϭ 279.5, JF-H ϭ 19.0 Hz, 1 F, CFa)
ppm. MS (DIS EI, 70 eV): m/z (%) ϭ 250 (7) [Mϩ·], 220 (22)
[C6H5O3F5ϩ·], 205 (100) [C6H6O2F5ϩ].
Supporting Information: Copies of 1H NMR spectra of compounds
1a, 1b, 3a, 3d, 6a, 6d, 7a, 7d and details on stereochemistry assign-
ment experiments (15 pages). See footnote on page 1.
Acknowledgments
5-Trifluoromethyldihydrofuran-2-one [(R)-1a]: Yield 62% from
(4S,5S)-7a, (Method A, b.p. ca. 80 °C). [α]2D0 ϭ Ϫ14 (c ϭ 0.7,
CHCl3). 1H NMR (CDCl3): δ ϭ 2.30Ϫ2.78 (m, 4 H, 3-H2 ϩ 4-
C.N.R. ‘‘Progetto Finalizzato per i Beni Culturali’’ and MURST
Cofin 2000 is gratefully acknowledged for financial support. Dr.
Alberto Arnone is gratefully acknowledged for skilful advice. Dr.
Alfonso Melloni thanks Politecnico of Milano for a scholarship.
3
3
H2), 4.78 (qdd, JH-F ϭ 6.2, J ϭ 1.8, 1.6 Hz, 1 H, 5-H) ppm. 13C
NMR (CDCl3): δ ϭ 21.2 (s, C-4), 26.2 (s, C-3), 75.0 (q, J ϭ
34.5 Hz, C-5), 123.5 (q, J ϭ 279.9 Hz, CF3), 174.7 (s, C-2) ppm.
3
19F NMR (CDCl3): δ ϭ Ϫ80.7 (d, JF-H ϭ 6.2 Hz) ppm. MS (GC
EI, 70 eV): m/z (%) ϭ 155 (3) [M ϩ H]ϩ, 154 (9) [Mϩ·], 107 (8)
[C3HO2F2ϩ], 95 (6) [C3H2F3ϩ], 85 (100) [C4H5O2ϩ], 69 (17) [CF3ϩ].
GC/MS: t1, m/z (%) ϭ 5.23 min, 154 (98) [Mϩ].
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