Asymmetric synthesis of long chain α-methyl-β-thiotrifluoromethyl ketones employing the SAMP-/RAMP-hydrazone alkylation methodology

Article abstract of DOI:10.1016/j.tetasy.2007.02.022

The enantioselective synthesis of both enantiomers of (Z)-1,1,1-trifluoro-3-methyl-4-thia-13-octadecen-2-one and (Z)-1,1,1-trifluoro-3-methyl-4-thia-13-hexadecen-2-one (ee ≥90%), potential inhibitors of the pheromone action of two major maize pests Sesamia nonagrioides and Ostrinia nubilalis, is described. The key step is based upon a stereoselective alkylation with methyl iodide using the SAMP-/RAMP-chiral auxiliary methodology, followed by deprotection under non-racemization conditions.

Full text of DOI:10.1016/j.tetasy.2007.02.022

Tetrahedron: Asymmetry 18 (2007) 651–658
Asymmetric synthesis of long chain a-methyl-b-thiotrifluoromethyl
ketones employing the SAMP-/RAMP-hydrazone
alkylation methodology
Lourdes Munoz, Ma Pilar Bosch and Angel Guerrero*
˜
Department of Biological Organic Chemistry, IIQAB (CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
Received 6 February 2007; accepted 20 February 2007
Available online 19 March 2007
Abstract—The enantioselective synthesis of both enantiomers of (Z)-1,1,1-trifluoro-3-methyl-4-thia-13-octadecen-2-one and (Z)-1,1,1-
trifluoro-3-methyl-4-thia-13-hexadecen-2-one (ee P90%), potential inhibitors of the pheromone action of two major maize pests Sesamia
nonagrioides and Ostrinia nubilalis, is described. The key step is based upon a stereoselective alkylation with methyl iodide using the
SAMP-/RAMP-chiral auxiliary methodology, followed by deprotection under non-racemization conditions.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
terase,9 chymotrypsin,10 trypsin,11 juvenile hormone ester-
ase,12 human liver microsomal carboxylesterases,13
cytosolic human phospholipase A214 or HIV-1 proteases.15
The fluorinated ketones function as transition-state ana-
logues of the enzyme, with the inhibition activity arising
from the formation of an adduct of tetrahedral geometry
between the serine residue, present at the active site of the
enzyme, with the highly electrophilic carbonyl moiety.16,17
Enzymatic inhibition is currently an area of crucial impor-
tance, particularly in the agrochemical and pharmaceutical
fields.1,2 Illustrative examples of the importance of enzyme
inhibitors are the development of inhibitors of human
neutrophil elastase for the treatment of pulmonary
emphysema,3 renin inhibitors as therapeutic agents for
hypertension related disorders,4 or inhibitors of neuro-
pathy target esterase, the target enzyme of several
neurotoxic organophosphorous compounds.5
We and others have previously shown that linear saturated
or unsaturated trifluoromethyl ketones (TFMKs) are good
antagonists of the pheromone activity in insects resulting in
potential biorational agents for pest control.18,1,19,8,20–23
This has been attributed, at least in part, to the inhibition
of the esterases present in male’s antennae.24,25,17 In this
context, introduction of a sulfur atom at a b-position to
the carbonyl group led to a new series of inhibitors of JH
esterase derived from the parent compound 3-octylthio-
1,1,1-trifluoropropan-2-one (OTFP) with a dramatically
enhanced potency.26 The activity is probably due to the
presence of an intramolecular hydrogen bond between
the free electron pair of sulfur with an OH group of the
hydrate.27,28 Introduction of a methyl group in alpha
position to the carbonyl of OTFP has shown a further
increase of the inhibitory potency in comparison to the
non-substituted compound.16
It is known that the introduction of fluorine atoms into a
bioactive molecule significantly alters the physicochemical
features of the molecule because of its high electronegativ-
ity. At the same time, it causes minimal steric alterations
and, hence, can facilitate the interactions of the molecule
with enzyme active sites, receptor sites, in transport mecha-
nisms and in other biological processes.6,4 Furthermore, the
presence of fluorine substituents in bioactive molecules
enhances their lipophilicities, thereby influencing the
‘in vivo’ uptake and transport of active ingredients.7,8 In
this context, fluorinated ketones are particularly attractive
from a pharmacological point of view as strong inhibitors
of a variety of serine hydrolases, including acetylcholines-
*
Following this trend, we herein report the racemic and
Corresponding author. Tel.: +34 934006120; fax: +34 932045904;
e-mail: agpqob@iiqab.csic.es
asymmetric synthesis of a-methyl-b-thiotrifluoromethyl
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.02.022

652
L. Mun˜oz et al. / Tetrahedron: Asymmetry 18 (2007) 651–658
i
R
OH
R
OH
89-93%
2a: R = Bu
2b: R = Et
3a,b
ii
90-94%
iii
R
SH
R
OTs
79-81%
4a,b
5a,b
78-82%
77-79% iv
v
R
S
COCF3
R
S
COCF3
Me
6a,b
1a,b
Scheme 1. Synthesis of b-thiotrifluoromethyl ketones 6a and 6b and ( )-a-methyl-b-thiotrifluoromethyl ketones 1a and 1b. Reagents and conditions: (i)
H2, P-2 Ni, EtOH; (ii) TsCl, Py; (iii) EtOC(S)SK, acetone, reflux, H2NCH2CH2NH2; (iv) DIPEA, BrCH2COCF3, CH2Cl2; (v) Et3N, CH3CH(Br)COCF3.
ketones (R)-1a, (R)-1b, (S)-1a, and (S)-1b, pheromone
inhibitors of two major pests of maize, the Mediterranean
corn borer Sesamia nonagrioides29,30 and the European
corn borer Ostrinia nubilalis,31,32 as new potential bio-
rational pest control agents.
SAMP-/RAMP-hydrazone methodology allows the estab-
lishment of the absolute configuration of the new chiral
compounds obtained.39–41
2. Results and discussion
R
S
COCF3
*
The synthesis of compounds 6a and 6b and racemics 1a and
1b was accomplished by alkylation of the intermediate
thiols 5a and 5b with 3-bromo-1,1,1-trifluoromethyl-2-
propanone or 3-bromo-1,1,1-trifluoromethyl-2-butanone,
respectively, in the presence of base42 in good yields
(Scheme 1). The latter bromo-substituted TFMK is not
commercially available but can be easily prepared by
acid-catalyzed bromination of 1,1,1-trifluoromethyl-2-
butanone in 85% yield.43 Thiols 5a and 5b were prepared
in a 3-step sequence from acetylenic alcohols 2a and 2b.
Thus, hydrogenation with P-2 Nickel afforded olefinic alco-
hols 3a and 3b in 89–93% yields with high stereochemical
purities (>97% Z, no E-isomer was detected by 13C
NMR). The next step, that is, the transformation of a hy-
droxyl group into a thiol, required the previous conversion
Me
1a: R = Bu
1b: R = Et
The racemic compounds can be obtained in a straight-
forward manner by condensation of the corresponding
thiol and 3-bromo-1,1,1-trifluoro-2-butanone. For the syn-
thesis of the chiral compounds, induction of chirality can
be accomplished using the SAMP-/RAMP-methodology
developed by Enders.33 (S)-(ꢀ)-1-Amino-2-methoxy-
pyrrolidine (SAMP) and (R)-(+)-1-amino-2-methoxypyrrol-
idine (RAMP) are commercially available chiral auxiliaries
and have been successfully applied in the asymmetric
synthesis of a number of bioactive natural products,34,35
in base to their high versatility in diastereotopic and
diastereofacial selective reactions.36–38 In addition, the
NR'2*
N
i
R
S
COCF3
R
S
CF3
74-77%
6a: R = Bu
6b: R = Et
(S)-7a (S)-7b
(R)-7a (R)-7b
79-86%
de = 92-94%
ii
NR'2*
CF3
N
iii
R
S
COCF3
R
S
*
*
79-81%
Me
Me
ee = 90-93%
(S)-1a (S)-1b
(R)-1a (R)-1b
(S,R)-8a (S,R)-8b
(R,S)-8a (R,S)-8b
NR'2* =
OCH3,
OCH3
N
N
Scheme 2. Asymmetric synthesis of chiral a-methyl-b-thiotrifluoromethyl ketones (S)-1a, (S)-1b, (R)-1a, (R)-1b. Reagents and conditions: (i) H2NNR02ꢁ,
65 ꢁC; (ii) LDA, CH3I, Et2O, ꢀ100 ꢁC; (iii) BF3ÆOEt2, (CH2O)n, acetone/H2O.

L. Mun˜oz et al. / Tetrahedron: Asymmetry 18 (2007) 651–658
653
into a good leaving group, such as a tosylate. This process
occurred under standard conditions to obtain tosylates 4a
and 4b in excellent yields. However, nucleophilic substitu-
tion of 4a under different conditions, that is, reaction with
thiourea,44 or with thioacetic acid, PPh3 and DIAD under
Mitsunobu conditions followed by reaction with LAH,45
led to the expected thiol mostly with the E configuration.
Much more convenient was the reaction with potassium
ethylxanthate in acetone at reflux for 30 min46 followed
by treatment with ethylenediamine.47 Under these condi-
tions, compounds 5a and 5b were obtained in 79–81%
yields with almost no double bond isomerization (Z:E,
94:6 for 5a and 93:7 for 5b).
chromatographic purification, hydrazones 7a and 7b were
isolated in 74–77% yields as pale yellow oils, which can
be safely stored under Ar in a refrigerator. Metallation of
the hydrazones with LDA in ether, followed by alkylation
of the resultant azaenolates with methyl iodide at ꢀ100 ꢁC,
afforded
a-methyl-b-thiotrifluoromethyl
hydrazones
(S,R)-8a, (S,R)-8b, (R,S)-8a, and (R,S)-8b in good yields
(79–86%) and high diastereomeric excess (92–94%), as
determined by 19F NMR (Table 1). Due to the uniform
diastereofacial differentiation common for all asymmetric
SAMP-/RAMP-hydrazone alkylations, the absolute con-
figuration which will predominate in the final product
can be safely predicted.48 The absolute configuration was
assigned by an analogy with previous results obtained with
b-sulfenylated ketones, as well as for the model currently
accepted for the relative topicity of electrophilic attack
onto lithium azaenolates derived from SAMP-hydraz-
ones.34,49 Therefore, the newly created stereogenic center
has an (R)-configuration, whereas the pyrrolidine stereo-
genic center maintained the original configuration of the
starting non-methylated hydrazones. Similarly, the alkyl-
ation product with the (S) configuration at the new stereo-
genic center can be obtained from the RAMP-hydrazone.
Remarkably, no N-, di- or poly-alkylation side products
could be detected.
For the asymmetric synthesis of chiral a-methyl-b-thiotri-
fluoromethyl ketones 1a and 1b, we followed the procedure
depicted in Scheme 2. This involved transformation of the
starting ketones 6a and 6b to the corresponding SAMP- or
RAMP-hydrazones (S)-7a, (S)-7b, (R)-7a and (R)-7b, met-
allation followed by trapping of the intermediate azaeno-
lates with an electrophile, and then hydrazone cleavage.
It is interesting to note that this type of reaction had never
been performed on b-thiotrifluoromethyl ketones.
Therefore, SAMP-hydrazones 7a and 7b were prepared by
heating b-thiotrifluoromethyl ketones 6a and 6b with
1.1 equiv of the aminopyrrolidines SAMP (Acros, 97%
ee) or RAMP (Aldrich, 99% ee) at 65 ꢁC for 48 h. After
In order to preserve the enantiomeric excess of the chiral
a-substituted trifluoromethyl ketones (S)-1a, (S)-1b,
Table 1. Yields and enantiomeric excess of compounds 7a and 7b, 8a and 8b, and 1a and 1b
Entry
Starting product
Hydrazone
Yield (%)
Methylated hydrazone
Yield (%)
Final product
Yield (%)
Prod.
Prod.
dea (%)
Prod.
eeb (%)
1
2
3
4
6a
6a
6b
6b
(S)-7a
(R)-7a
(S)-7b
(R)-7b
74
77
75
74
(S,R)-8a
(R,S)-8a
(S,R)-8b
(R,S)-8b
86
79
83
79
92
92
94
92
(R)-1a
(S)-1a
(R)-1b
(S)-1b
79
81
81
80
90
90
93
90
a Determined by 19F NMR.
b Determined by chiral GC on a Cydex-B 0.25 column.
Figure 1. Enantiomeric resolution of ( )-1b, (R)-1b, and (S)-1b (from left to right) by chiral GC using a Cydex-B 0.25 column (25 m · 0.22 mm).

654
L. Mun˜oz et al. / Tetrahedron: Asymmetry 18 (2007) 651–658
(R)-1a, and (R)-1b, the hydrolysis procedure must take
place without any racemization at the newly generated ste-
reogenic center. Classical cleavage procedures, such as
heating with acid or base,50 cannot be used, since the sen-
sitive chiral a-methyl ketones rapidly racemize under these
conditions. In the same vein, oxidative cleavage of the
C@N double bond of SAMP-hydrazones with ozone48
was also impractical on our substrates for the presence of
a double bond in the molecule. Another common possibil-
ity of cleavage is methylation with an excess of methyl
iodide followed by hydrolysis with 3 M HCl (‘salt
method’)51 but, in our case, only mixtures of decomposi-
tion products were obtained. Finally, the use of boron tri-
fluoride-ether in acetone:water followed by the addition of
paraformaldehyde52 allowed us to obtain the desired a-
methyl ketones 1a and 1b in good yields (79–81%). To
establish their enantiomeric excesses, several attempts were
carried out without success. Thus, neither NMR experi-
ments with tris[3-(trifluoromethylhydroxymethylen)-(+)-
camphorato] europium(III) nor resolution by HPLC with
a Chiralcel OD (250 mm · 4.6 mm) column resulted in an
efficient separation of the enantiomers of the racemic ( )-
1b. Finally, determination of the enantiomeric excess of
the ketones (S)-1a, (S)-1b, (R)-1a, and (R)-1b was success-
fully accomplished by chiral GC analysis using a Cydex-B
0.25 column (25 m · 0.22 mm) (Fig. 1). In this way, the ee
of all enantiomers could be finally calculated. The results
are summarized in Table 1.
spectrometer. Optical rotations were measured on a
Perkin–Elmer 341 polarimeter. Calculations of the diaste-
reomeric excesses were carried out by 19F NMR, whereas
the enantiomeric excesses were determined by chiral GC
using a Cydex-B 0.25 column (25 m · 0.22 mm).
4.2. Synthesis of b-thiotrifluoromethyl ketones 6a and 6b
4.2.1. (Z)-9-Tetradecen-1-ol 3a.53 P-2 Nickel was pre-
pared as previously described by Brown and Ahuja.54
Under a hydrogen atmosphere, 9-tetradecyn-1-ol (3.55 g,
16.90 mmol) was added to the catalyst solution in ethanol
(10 ml). After stirring for 2 h at room temperature, the
solution was filtered through Celite and the filtrate repeat-
edly washed with hexane. The solvent was evaporated and
the crude again diluted with hexane. The organic layer was
washed with brine, dried over MgSO4 and the solvent
removed to afford 3.34 g (93%) of 3a as a colorless oil.
1
The E-isomer was not detected by 13C NMR. H NMR
(300 MHz, CDCl3): d 5.34 (m, 2H); 3.63 (t, J = 6.0 Hz,
2H); 2.01 (m, 4H); 1.56 (m, 2H); 1.33 (b, 14H); 0.89 (t,
J = 6.9 Hz) ppm. 13C NMR (75 MHz, CDCl3): d 129.9
(CH); 129.8 (CH); 63.1; 32.8; 31.9; 29.7; 29.5; 29.4; 29.2;
27.1; 26.9; 25.7; 22.3; 14.0 (CH3) ppm. IR (film) m: 3464,
3008, 2929, 2860, 1464, 1055, 729 cmꢀ1. MS (EI): m/z
(%) 212 (M+, 1); 194 (23); 166 (13); 109 (36); 95 (76); 81
(72); 67 (100); 55 (98).
4.2.2. (Z)-9-Dodecen-1-ol 3b.53 Alcohol 3b was prepared
in the same way as 3a. Starting from 9-dodecyn-1-ol
(3.00 g, 16.46 mmol) and Ni(OAc)2Æ4H2O (0.52 g,
2.14 mmol), the desired product 3b (2.70 g, 89%) was ob-
tained as a colorless oil. The E isomer was not detected
3. Conclusion
The enantioselective a-methylation of b-thiotrifluoro-
methyl ketones, through the SAMP-/RAMP-chiral auxil-
iary method, presented in this paper opens up a practical
entry to this important class of optically active compounds
previously unknown in the literature. Following this meth-
odology and as representative examples, both enantiomers
of two pheromone antagonists of two major maize insect
pests have been synthesized in good overall chemical yields
and excellent enantioselectivities. These compounds are
now ready for biological activity as new putative bio-
rational pest control agents.
1
by 13C NMR. H NMR (300 MHz, CDCl3): d 5.32 (m,
2H); 3.61 (t, J = 6.6 Hz, 2H); 2.02 (m, 4H); 1.73 (s, 1H);
1.55 (m, 2H); 1.26 (b, 10H); 0.94 (t, J = 7.5 Hz, 3H)
ppm. 13C NMR (75 MHz, CDCl3): d 131.5 (CH); 129.2
(CH); 62.9; 32.7; 29.7; 29.4; 29.4; 29.2; 27.0; 25.7; 20.4;
14.3 (CH3) ppm. IR (film) m: 3403, 3005, 2930, 1461,
1052, 909, 740, 649 cmꢀ1. MS (EI) m/z (%): 184 (M+,
0.5); 166 (7); 110 (30); 109 (34); 96 (78); 95 (88); 82 (96);
81 (99); 69 (85); 68 (96); 67 (100); 55 (99); 41 (92).
4.2.3. (Z)-1-(p-Toluenesulfonyl)-9-tetradecene 4a.55
A
4. Experimental
4.1. General
solution of alcohol 3a (1.00 g, 4.64 mmol), tosyl chloride
(2.65 g, 13.90 mmol) and 10 ml of anhydrous pyridine were
placed in a round bottomed flask and cooled to 0 ꢁC for
12 h. Then, the solution was acidified with 0.1 M HCl
and extracted with hexane. The combined organic layers
were washed with brine and dried. Solvent evaporation
afforded compound 2 (1.562 g, 90% yield) without the need
n-Butyllithium (1.6 M in hexane), BF3ÆOEt2 and SAMP
were purchased from Aldrich. RAMP was obtained from
Acros Organics. All reactions employing organometallic
compounds were carried out under Ar. All solvents were
dried and distilled according to standard procedures. IR
spectra were recorded on a Bomen MB-120 or on a Nicolet
Avatar 360 FT-IR spectrometer. NMR spectra were
recorded at 200, 300, 400 or 500 MHz for 1H, 75 or
100 MHz for 13C and 282 MHz for 19F, on Varian Gemini
200, Varian Unity 300, Varian Mercury 400 or Varian
Inova 500 spectrometers. Mass spectra (MS) were obtained
on a Fisons MD 800 instrument and high resolution mass
spectra (HRMS) on an Autospec-Q Micromass-Ltd UK
1
for further purification. H NMR (200 MHz, CDCl3): d
7.77 (d, J = 8.4 Hz, 2H); 7.32 (d, J = 8.4 Hz, 2H); 5.32
(m, 2H); 3.99 (t, J = 6.4 Hz, 2H); 2.42 (s, 3H); 1.97 (m,
4H); 1.59 (m, 2H); 1.27 (b, 14H); 0.94 (t, J = 7.5 Hz, 3H)
ppm. 13C NMR (75 MHz, CDCl3): d 144.5 (C); 133.1
(C); 129.8 (CH); 129.7 (2CH); 129.6 (CH); 127.8 (2CH);
70.6; 31.9; 29.6; 29.2; 29.0; 28.8; 28.7; 27.0; 26.8; 25.2;
22.2; 21.5 (CH3); 13.9 (CH3) ppm. IR (film) m: 3004,
2924, 1362, 1189, 664, 493 cmꢀ1. MS (EI) m/z (%): 366
(M+, 1); 195 (11); 194 (73); 173 (35); 155 (29); 138 (36);

L. Mun˜oz et al. / Tetrahedron: Asymmetry 18 (2007) 651–658
655
124 (55); 110 (88); 96 (95); 95 (93); 91 (93); 82 (98); 81 (100);
67 (93); 55 (92); 41 (82).
4.2.7. (Z)-1,1,1-Trifluoro-4-thia-13-octadecen-2-one 6a. To
a solution of thiol 5a (0.42 g, 1.86 mmol) in 20 ml of anhyd
CH2Cl2 were added diisopropylethylamine (0.3 ml,
1.86 mmol) and 3-bromo-1,1,1-trifluoro-2-propanone19
(0.53 g, 2.79 mmol). The mixture was stirred at room tem-
perature for 4 h. The solvent was evaporated at reduced
pressure and the crude purified by column chromatography
(silica, hexane:ether, 90:10) to afford 0.50 g (79%) of the
expected product 6a, as a mixture of ketone and hydrate
in a 45:55 ratio. 1H NMR (300 MHz, CDCl3): d 5.32
(m, 2H); 4.12 (s, 2H, –C(OH)2); 3.45 (s, 2H, –SCH2CO–);
2.86 (s, 2H, –SCH2C(OH)2–); 2.68 (t, J = 7.5 Hz, 2H,
–CH2SCH2C(OH)2–); 2.48 (t, J = 7.2 Hz, 2H, –CH2S-
CH2CO–); 1.99 (m, 4H); 1.55 (m, 2H); 1.29 (b, 14H); 0.95
(t, J = 7.5 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): d
185.0 (q, J = 35 Hz, –COCF3); 129.9 (CH); 129.7 (CH);
122.9 (q, J = 285 Hz, –C(OH)2CF3); 115.5 (q, J = 291 Hz,
–COCF3); 92.4 (q, J = 32 Hz, –C(OH)2CF3); 36.5; 34.7;
33.6; 31.9; 29.7; 29.3; 29.3; 29.2; 29.2; 29.1; 29.0; 28.6;
28.6; 28.5; 27.1; 26.9; 22.3; 14.4 (CH3) ppm. 19F NMR
(282 MHz, CDCl3): d ꢀ76.2 (s, 3F, –COCF3); ꢀ85.8 (s,
3F, –C(OH)2CF3) ppm. IR (film) m: 3424, 3005, 2927,
2857, 1747, 1188 cmꢀ1. MS (EI) m/z (%): 338 (M+, 0.5);
269 (2); 241 (4); 227 (94); 184 (4); 171 (7); 157 (13); 143
(9); 129 (18); 115 (16); 109 (16); 101 (30); 95 (39); 87 (39);
81 (48); 69 (55); 67 (52); 55 (100); 41 (55). HRMS Calcd
for C17H29F3OS (M+): 338.1891; Found: 338.1890.
4.2.4. (Z)-1-(p-Toluenesulfonyl)-9-dodecene 4b. A proce-
dure identical to that described above for 4b was followed.
Thus, from alcohol 3b (2.72 g, 14.74 mmol), tosyl chloride
(8.41 g, 44.22 mmol) and pyridine (39 ml), compound 4b
was obtained (4.69 g, 94%) without the need for further
purification. 1H NMR (300 MHz, CDCl3): d 7.78 (d,
J = 8.4 Hz, 2H); 7.33 (d, J = 8.4 Hz, 2H); 5.32 (m, 2H);
4.01 (t, J = 6.6 Hz, 2H); 2.44 (s, 3H); 2.02 (m, 4H); 1.62
(m, 2H); 1.25 (b, 10H); 0.94 (t, J = 7.5 Hz, 3H) ppm. 13C
NMR (75 MHz, CDCl3): d 144.6 (C); 133.2 (C); 131.5
(CH); 129.7 (2CH); 129.1 (CH); 127.8 (2CH); 70.6;
29.6; 29.2; 29.0; 28.8; 28.7; 27.0; 25.3; 21.6 (CH3); 20.4;
14.3 (CH3) ppm. IR (film) m: 3002, 2930, 1358, 1181, 909,
739, 651, 554 cmꢀ1. MS (EI) m/z (%): 338 (M+, 1); 173
(45); 166 (83); 154 (41); 137 (26); 124 (54); 110 (81); 95
(89); 91 (97); 82 (100); 81 (93); 68 (95); 67 (95); 55 (89);
41 (88).
4.2.5. (Z)-9-Tetradecene-1-thiol 5a. Tosylate 4a (1.52 g,
4.14 mmol) was added to a solution of potassium ethylxant-
hate (1.03 g, 6.21 mmol) in acetone (15 ml) and the mixture
was refluxed for 30 min.46 Then, the solution was allowed to
cool to room temperature, the potassium salt was filtered
and the solvent evaporated. Chloroform was added to the
residue. The organic layer was washed with brine, dried
and evaporated to dryness. The crude xanthogenic ester
was decomposed at room temperature to the corresponding
thiol by stirring with ethylenediamine (4 ml) for 30 min.47
The solution was acidified with 0.1 M HCl and extracted
with hexane. The combined organic layers were washed
with brine and dried. The crude material was purified by
column chromatography (silica, hexane) to obtain 0.75 g
(79%) of thiol 5a, partially isomerized (Z:E, 94:6) as deter-
4.2.8. (Z)-1,1,1-Trifluoro-4-thia-13-hexadecen-2-one 6b.23
A procedure identical to that described above for 6a was
followed. Starting from thiol 5b (0.20 g, 1.00 mmol),
diisopropylethylamine (0.17 ml, 1.00 mmol), and 3-bromo-
1,1,1-trifluoro-2-propanone (0.28 g, 1.50 mmol), the
expected product 6b (0.24 g, 77%) was obtained, after puri-
fication, as a mixture of ketone and hydrate in a 45:55 ratio.
1H NMR (300 MHz, CDCl3): d 5.34 (m, 2H); 3.87 (s, 2H,
–C(OH)2); 3.48 (s, 2H, –SCH2CO–); 2.90 (s, 2H, –SCH2-
C(OH)2–); 2.71 (t, J = 7.2 Hz, 2H, –CH2SCH2C(OH)2–);
2.51 (t, J = 7.5 Hz, 2H, –CH2SCH2CO–); 2.03 (m, 4H);
1.59 (m, 2H); 1.34 (b, 10H); 0.95 (t, J = 7.5 Hz, 3H) ppm.
13C NMR (75 MHz, CDCl3): d 185.1 (q, J = 34 Hz,
–COCF3); 131.6 (CH); 129.2 (CH); 122.9 (q, J = 284 Hz,
–C(OH)2CF3); 115.5 (q, J = 290 Hz, –COCF3); 92.4 (q,
J = 32 Hz, –C(OH)2CF3); 36.4; 34.8; 33.6; 31.9; 29.7; 29.3;
29.3; 29.1; 29.1; 29.0; 28.6; 28.6; 28.5; 27.0; 20.5; 14.4
(CH3) ppm. 19F NMR (282 MHz, CDCl3): d ꢀ76.3 (s, 3F,
–COCF3); ꢀ86.0 (s, 3F, –C(OH)2CF3) ppm. IR (film) m:
3423, 3005, 2928, 2854, 1746, 1182 cmꢀ1. MS (EI) m/z
(%): 310 (M+, 1); 241 (2); 199 (79); 157 (9); 129 (15); 115
(15); 109 (15); 101 (29); 95 (33); 87 (40); 81 (48); 69 (71);
67 (70); 55 (100); 41 (85), HRMS Calcd for C15H25F3OS
(M+): 310.1578; Found: 310.1567.
1
mined by 13C NMR. H NMR (200 MHz, CDCl3): d 5.34
(m, 2H); 2.51 (dt, J1 = J2 = 7.6 Hz, 2H); 1.98 (m, 4H);
1.59 (m, 2H); 1.28 (b, 14H); 0.95 (t, J = 7.5 Hz, 3H) ppm.
13C NMR (75 MHz, CDCl3): d 129.9 (CH); 129.8 (CH);
34.0; 31.9; 29.7; 29.4; 29.2; 29.0; 28.3; 27.1; 26.9; 24.6;
22.3; 14.0 (CH3) ppm. IR (film) m: 3004, 2926, 1460,
718 cmꢀ1. MS (EI) m/z (%): 230 [(M+2)+, 0.6]; 228 (M+,
10); 227 (15); 199 (7); 185 (25); 171 (27); 157 (16); 143
(32); 129 (45); 115 (73); 101 (99); 87 (100); 81 (79); 69
(82); 67 (83); 55 (90); 41 (79).
4.2.6. (Z)-9-Dodecene-1-thiol 5b. Following a similar pro-
cedure as for 5a, tosylate 4b (0.50 g, 1.48 mmol), potassium
ethylxanthate (0.36 g, 2.22 mmol) and ethylenediamine
(3.5 ml) afforded thiol 5b (0.24 g, 81%) after column chro-
matography purification. This compound was partially
isomerized (Z:E, 93:7) as determined by 13C NMR. 1H
NMR (300 MHz, CDCl3): d 5.33 (m, 2H); 2.51 (dt,
J1 = J2 = 7.5 Hz, 2H); 2.01 (m, 4H); 1.58 (m, 2H); 1.33
(b, 10H); 0.95 (t, J = 7.5 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d 131.5 (CH); 129.2 (CH); 34.0; 29.7;
29.4; 29.2; 29.0; 28.3; 27.0; 24.6; 20.5; 14.4 (CH3) ppm.
IR (film) m: 3005, 2929, 1463, 909, 734, 650 cmꢀ1. MS
(EI) m/z (%): 202 [(M+2)+, 6]; 200 (M+, 10); 199 (21);
157 (42); 143 (63); 129 (59); 115 (71); 101 (99); 87 (100);
69 (77); 68 (73); 67 (84); 55 (90); 41 (90).
4.3. Synthesis of ( )-1a,b
4.3.1. ( )-(Z)-1,1,1-Trifluoro-3-methyl-4-thia-13-octadecen-
2-one ( )-1a. To a solution of thiol 5a (0.32 g, 1.41 mmol)
in anhyd CH2Cl2 (11 ml) were added Et3N (0.2 ml,
1.41 mmol) and 3-bromo-1,1,1-trifluoro-2-butanone (0.32,
1.55 mmol).56 The mixture was stirred at room temperature
for 1 h. The solvent was then evaporated off and the residue
extracted with hexane, washed with satd soln of NaHCO3,

656
L. Mun˜oz et al. / Tetrahedron: Asymmetry 18 (2007) 651–658
brine and dried over MgSO4. Purification of the crude by
column chromatography (silica, hexane) afforded 0.41 g
(82%) of racemic 1a as a colorless oil. 1H NMR
(300 MHz, CDCl3): d 5.34 (m, 2H); 3.75 (q, J = 6.9 Hz,
1H); 2.49 (dt, J1 = 11.7 Hz, J2 = 7.5 Hz, 1H); 2.32 (dt,
J1 = 12.0 Hz, J2 = 7.2 Hz, 1H); 2.02 (m, 4H); 1.54 (m,
2H); 1.50 (d, J = 6.9 Hz, 3H); 1.32 (b, 14H); 0.89 (t,
J = 6.9 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): d
185.9 (q, J = 33 Hz, COCF3); 129.9 (CH); 129.8 (CH);
115.9 (q, J = 291 Hz, COCF3); 40.9 (CH); 31.9; 29.7;
29.3; 29.1; 29.0; 28.8; 28.5; 27.1; 26.9; 22.3; 14.7 (CH3);
14.0 (CH3) ppm. 19F NMR (282 MHz, CDCl3): d ꢀ74.9
(s, 3F, –COCF3) ppm. IR (film) m: 3004, 2928, 2856,
1742, 1458, 1276, 1203, 1154, 699 cmꢀ1. MS (EI) m/z
(%): 352 (M+, 1); 255 (35); 227 (100); 141 (13); 129 (18);
115 (27); 109 (46); 101 (50); 97 (36); 95 (82); 87 (73); 81
(87); 75 (78); 69 (87); 55 (96); 43 (43); 41 (78). HRMS Calcd
for C18H31F3OS (M+): 352.2048; Found: 352.2039.
J = 32 Hz, CNCF3); 122.1 (q, J = 272 Hz, CNCF3); 74.3;
65.9 (CH); 59.2 (CH3); 53.3; 33.3; 31.9; 29.7; 29.4; 29.3;
29.2; 29.1; 28.8; 27.2; 27.1; 26.9; 26.1; 23.9; 22.3; 14.0
(CH3) ppm. 19F NMR (282 MHz, CDCl3): d ꢀ66.8 (s, 3F,
–CNCF3) ppm. IR (film) m: 3005, 2927, 2855, 1600, 1460,
1368, 1326, 1226, 1156, 1101, 1041 cmꢀ1. MS (EI) m/z
(%): 452 [(M+2)+, 5]; 450 (M+, 35); 407 (34); 406 (100);
336 (9); 308 (5); 224 (30); 223 (44), 207 (37); 191 (15); 179
(50); 177 (52); 150 (14); 123 (29); 112 (37); 95 (40); 87
(40); 71 (40); 69 (41); 67 (44); 55 (46); 41 (46).
4.4.2.
of (Z)-1,1,1-trifluoro-4-thia-13-octadecen-2-one (R)-7a.
(R)-(ꢀ)-[20-Methoxymethylpyrrolidinyl]hydrazone
A
procedure identical to that described above for (S)-7a was
followed, starting from 6a (50 mg, 0.15 mmol) and (R)-
(+)-1-amino-2-methoxymethylpyrrolidine (21 ll, 0.16 mmol).
After purification, the corresponding hydrazone (R)-7a was
20
obtained (52 mg, 77%) as a light yellow oil, ½aꢂD = ꢀ139.5 (c
0.99, CHCl3), ee 99%. The spectroscopic data are identical
4.3.2. ( )-(Z)-1,1,1-Trifluoro-3-methyl-4-thia-13-hexadecen-
2-one ( )-1b. A procedure identical to that described
above for 1a was used. Starting from thiol 5b (0.20 g,
0.98 mmol), Et3N (0.10 ml, 0.98 mmol), and 3-bromo-
1,1,1-trifluoro-2-butanone (0.22 g, 1.08 mmol), racemic 1b
was obtained as a colorless oil after purification on column
chromatography (0.25 g, 78%). 1H NMR (300 MHz,
CDCl3): d 5.34 (m, 2H); 3.76 (q, J = 6.9 Hz, 1H); 2.49
(dt, J1 = 12.0 Hz, J2 = 7.2 Hz, 1H); 2.32 (dt, J1 =
12.3 Hz, J2 = 7.2 Hz, 1H); 2.02 (m, 4H); 1.54 (m, 2H);
1.50 (d, J = 6.9 Hz, 3H); 1.32 (b, 10H); 0.95 (t,
J = 7.5 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): d
185.9 (q, J = 33 Hz, COCF3); 131.6 (CH); 129.2 (CH);
115.9 (q, J = 291 Hz, COCF3); 40.9 (CH); 29.7; 29.3;
29.1; 29.0; 28.8; 28.5; 27.0; 20.5; 14.7 (CH3); 14.4 (CH3)
ppm. 19F NMR (282 MHz, CDCl3): d ꢀ74.9 (s, 3F,
–COCF3) ppm. IR (film) m: 3004, 2929, 2856, 1742, 1458,
1276, 1205, 1152, 699 cmꢀ1. MS (EI) m/z (%): 324 (M+,
10); 255 (4); 227 (65); 199 (85); 171 (14); 157 (12); 155
(16); 143 (26); 141 (33); 129 (44); 123 (56); 115 (53); 109
(72); 97 (56); 95 (85); 87 (75); 81 (86); 75 (76); 69 (82); 67
(90); 55 (86); 43 (53); 41 (100). HRMS Calcd for
C16H27F3OS (M+): 324.1735; Found: 324.17447.
to those of the enantiomeric hydrazone (S)-7a.
4.4.3. (S)-(+)-[20-Methoxymethylpyrrolidinyl]hydrazone of
(Z)-1,1,1-trifluoro-4-thia-13-hexadecen-2-one
procedure identical to that described above for (S)-7a was
followed, starting from 6b (200 mg, 0.77 mmol) and
(S)-(+)-1-amino-2-methoxymethylpyrrolidine (110 ll, 0.84
mmol). After purification, the corresponding hydrazone
(S)-7b. A
(S)-7b was obtained (201 mg, 75%) as a light yellow oil,
20
½aꢂD = +162.9 (c 1.15, CHCl3), ee 97%. 1H NMR
(500 MHz, CDCl3): d 5.33 (m, 2H); 3.57 (m, 7H); 3.35 (s,
3H); 2.56 (t, J = 7.5 Hz, 2H); 1.99 (m, 6H); 1.78 (m, 2H);
1.57 (m, 2H); 1.31 (b, 10H); 0.95 (t, J = 7.8 Hz, 3H) ppm.
13C NMR (100 MHz, CDCl3): d 131.6 (CH); 129.2 (CH);
126.5 (q, J = 32 Hz, CNCF3); 122.1 (q, J = 272 Hz,
CNCF3); 74.3; 65.9 (CH); 59.2 (CH3); 53.3; 33.3; 29.7;
29.4; 29.3; 29.2; 29.1; 28.8; 27.2; 27.0; 26.1; 23.9; 20.5; 14.4
(CH3) ppm. 19F NMR (282 MHz, CDCl3): d ꢀ66.8 (s, 3F,
–CNCF3) ppm. IR (film) m: 3004, 2927, 2855, 1599, 1461,
1368, 1326, 1226, 1189, 1154, 1102, 1040 cmꢀ1. MS (EI)
m/z (%): 424 [(M+2)+, 1]; 422 (M+, 15); 379 (7); 378 (22);
377 (100); 223 (16); 179 (57); 177 (62); 150 (5); 123 (10);
112 (13); 95 (20); 87 (23); 81 (19); 69 (41); 55 (66); 45 (31);
41 (60).
4.4. Asymmetric synthesis of (R)-1a, (S)-1a, (R)-1b,
and (S)-1b
4.4.4. (R)-(ꢀ)-[20-Methoxymethylpyrrolidinyl]hydrazone of
(Z)-1,1,1-trifluoro-4-thia-13-hexadecen-2-one [(R)-7b].
A
4.4.1. (S)-(+)-[20-Methoxymethylpyrrolidinyl]hydrazone of
procedure identical to that described above for (S)-7a
was followed, starting from 6b (142 mg, 0.46 mmol) and
(R)-(+)-1-amino-2-methoxymethylpyrrolidine (68 ll, 0.50
mmol). After purification on column chromatography,
(Z)-1,1,1-trifluoro-4-thia-13-octadecen-2-one
(S)-7a.
A
mixture of 6a (155 mg, 0.46 mmol) and (S)-(ꢀ)-1-amino-
2-methoxymethylpyrrolidine (68 ll, 0.50 mmol) was stirred
at 65 ꢁC for 48 h. When the reaction was complete, the mix-
ture was poured into hexane–H2O. The aqueous layer was
extracted with hexane, the organic layers were combined,
washed with brine and dried over MgSO4. After concentra-
tion in vacuo, the crude product was purified by column
the corresponding hydrazone (R)-7b was obtained
20
(144 mg, 74%) as a light yellow oil, ½aꢂD = ꢀ156.4 (c 1.17,
CHCl3), ee 99%. The spectroscopic data are identical to
those of the enantiomeric hydrazone (S)-7b.
chromatography (silica gel, hexane–Et2O, 98:2) to afford
4.4.5.
(20S,3R)-(+)-[20-Methoxymethylpyrrolidinyl]hydr-
20
(S)-7a (152 mg, 74%) as a light yellow oil, ½aꢂD = +138.5
azone of (Z)-1,1,1-trifluoro-3-methyl-4-thia-13-octadecen-2-
one (S,R)-8a. A solution of 1.5 M n-BuLi in n-hexane (0.2
ml, 0.27 mmol) was added dropwise at 0 ꢁC under Ar, via a
syringe, to a 0.4 M soln of diisopropylamine in ether (38 ll,
0.27 mmol) and stirred for 15 min. Compound (S)-7a
(115 mg, 0.26 mmol) was added dropwise and the mixture
1
(c 1.43, CHCl3), ee 97%. H NMR (400 MHz, CDCl3): d
5.34 (m, 2H); 3.57 (m, 7H); 3.35 (s, 3H); 2.56 (t,
J = 7.6 Hz, 2H); 2.01 (m, 6H); 1.78 (m, 2H); 1.57 (m, 2H);
1.32 (b, 14H); 0.89 (t, J = 6.8 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3): d 129.9 (CH); 129.8 (CH); 126.5 (q,

L. Mun˜oz et al. / Tetrahedron: Asymmetry 18 (2007) 651–658
657
stirred at 0 ꢁC for 15 min more and cooled to ꢀ100 ꢁC.
Then MeI (17 ll, 0.27 mmol) was added, stirred further
for 1 h at this temperature and allowed to warm up to
room temperature for 2 h. The solvent was removed, water
was added and the organic material extracted with hexane.
After drying over MgSO4, concentration under vacuum left
an oil which was purified by column chromatography on
above for (S,R)-8a was followed from (R)-7b (125 mg,
0.30 mmol). After purification, the corresponding product
(R,S)-8b was obtained as a light yellow oil (103 mg,
20
79%), ½aꢂD = ꢀ248.8 (c 1.29, CHCl3), de 92%. The spectro-
scopic data are identical to those of the enantiomeric
hydrazone (S,R)-8b.
silica gel (hexane–ether, 98:2) to afford (S,R)-8a (104 mg,
4.4.9. (R)-(ꢀ)-(Z)-1,1,1-Trifluoro-3-methyl-4-thia-13-octa-
decen-2-one (R)-1a. To a soln of hydrazone (S,R)-8a
(70 mg, 0.15 mmol) in acetone (7 ml) and water (0.6 ml)
was added BF3ÆOEt2 (57 ll, 0.45 mmol) dropwise at room
temperature. Paraformaldehyde (23 mg, 0.75 mmol) was
then added, and the reaction mixture stirred for 12 h.
The solvent was removed in vacuum, and the residue taken
up in ether, washed with NH4Cl satd soln and brine, and
dried over MgSO4. After evaporation of the solvent, the
crude was purified by column chromatography (silica,
20
86%) as a yellow oil, ½aꢂD = +205.1 (c 0.96, CHCl3), de
1
92%. H NMR (400 MHz, CDCl3): d 5.34 (m, 2H); 4.22
(q, J = 7.2 Hz, 1H); 3.48 (m, 5H); 3.35 (s, 3H); 2.54 (t,
J = 7.2 Hz, 2H); 1.94 (m, 6H); 1.74 (m, 2H); 1.57 (m,
2H); 1.49 (d, J = 7.2 Hz, 3H); 1.30 (b, 14H); 0.89 (t,
J = 6.8 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): d
137.1 (q, J = 30 Hz, CNCF3); 129.9 (CH); 129.8 (CH);
121.8 (q, J = 275 Hz, CNCF3); 74.2; 66.7 (CH); 59.1
(CH3); 55.2; 36.5 (CH); 32.2; 31.9; 29.7; 29.4; 29.3; 29.2;
28.9; 27.1; 26.9; 26.2; 23.8; 22.3; 18.6 (CH3); 14.0 (CH3)
ppm. 19F NMR (282 MHz, CDCl3): d ꢀ62.5 (s, 3F,
–CNCF3) ppm. IR (film) m: 3003, 2927, 2855, 1591, 1459,
1378, 1328, 1286, 1157, 1112, 1016 cmꢀ1. MS (EI) m/z
(%): 466 [(M+2)+, 6]; 464 (M+, 41); 421 (16); 420 (81);
350 (26); 308 (7); 295 (16); 267 (18); 237 (100); 225 (22);
207 (22); 193 (35); 192 (26); 191 (45); 177 (35); 142 (17);
123 (21); 112 (35); 87 (34); 69 (60); 55 (40); 45 (41); 41 (45).
hexane) to afford (R)-1a (41 mg, 79%) as a colorless oil,
20
½aꢂD = ꢀ132.4 (c 1.36, CHCl3), ee 90%. 1H NMR
(300 MHz, CDCl3): d 5.34 (m, 2H); 3.75 (q, J = 6.9 Hz,
1H); 2.49 (dt, J1 = 11.7 Hz, J2 = 7.5 Hz, 1H); 2.32 (dt,
J1 = 12.0 Hz, J2 = 7.2 Hz, 1H); 2.02 (m, 4H); 1.54 (m,
2H); 1.50 (d, J = 6.9 Hz, 3H); 1.32 (b, 14H); 0.89 (t,
J = 6.9 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): d
185.9 (q, J = 33 Hz, COCF3); 129.9 (CH); 129.8 (CH);
115.9 (q, J = 291 Hz, COCF3); 40.9 (CH); 31.9; 29.7;
29.3; 29.1; 29.0; 28.8; 28.5; 27.1; 26.9; 22.3; 14.7 (CH3);
14.0 (CH3) ppm. 19F NMR (282 MHz, CDCl3): d ꢀ74.9
(s, 3F, –COCF3) ppm. IR (film) m: 3004, 2928, 2856,
1742, 1458, 1276, 1203, 1154 cmꢀ1. MS (EI) m/z (%): 352
(M+, 1); 283 (1); 255 (36); 227 (100); 213 (16); 199 (10);
185 (15); 171 (25); 157 (26); 143 (31); 142 (10); 141 (32);
129 (33); 123 (38); 115 (35); 109 (47); 101 (40); 97 (36); 95
(55); 81 (61); 69 (75); 55 (98); 43 (38); 41 (61). HRMS Calcd
for C18H31F3OS (M+): 352.2048; Found: 352.2036.
4.4.6.
(20R,3S)-(ꢀ)-[20-Methoxymethylpyrrolidinyl]hydr-
azone of (Z)-1,1,1-trifluoro-3-methyl-4-thia-13-octadecen-2-
one (R,S)-8a. A procedure identical to that described
above for (S,R)-8a was followed from (R)-7a (34 mg,
0.08 mmol). After purification, the corresponding product
(R,S)-8a was obtained as a light yellow oil (28 mg, 79%),
20
½aꢂD = ꢀ203.2 (c 1.06, CHCl3), de 92%. The spectroscopic
data are identical to those of the enantiomeric hydrazone
(S,R)-8a.
4.4.7.
(20S,3R)-(+)-[20-Methoxymethylpyrrolidinyl]hydr-
4.4.10. (S)-(+)-(Z)-1,1,1-Trifluoro-3-methyl-4-thia-13-octa-
decen-2-one (S)-1a. A procedure identical to that de-
scribed above for (R)-1a was followed from (R,S)-8a
(15 mg, 0.03 mmol). After purification, ketone (S)-1a
azone of (Z)-1,1,1-trifluoro-3-methyl-4-thia-13-hexadecen-2-
one (S,R)-8b. A procedure identical to that described
above for (S,R)-8a was followed from (S)-7b (173 mg,
0.40 mmol). After purification, the corresponding product
(S,R)-8b was obtained as a light yellow oil (150 mg,
(9 mg, 81%) was obtained as
a
colorless oil,
20
½aꢂD = +126.5 (c 0.88, CHCl3), ee 90%. The spectroscopic
data are identical to those of the enantiomeric ketone
(R)-1a.
20
1
83%), ½aꢂD = +251.4 (c 1.02, CHCl3), de 94%. H NMR
(300 MHz, CDCl3): d 5.33 (m, 2H); 4.22 (q, J = 7.2 Hz,
1H); 3.48 (m, 5H); 3.35 (s, 3H); 2.54 (t, J = 7.5 Hz, 2H);
2.00 (m, 6H); 1.73 (m, 2H); 1.57 (m, 2H); 1.49 (d,
J = 7.2 Hz, 3H); 1.32 (b, 10H); 0.95 (t, J = 7.5 Hz, 3H)
ppm. 13C NMR (75 MHz, CDCl3): d 137.2 (q, J = 30 Hz,
CNCF3); 131.6 (CH); 129.2 (CH); 121.9 (q, J = 275 Hz,
CNCF3); 74.3; 66.7 (CH); 59.1 (CH3); 55.3; 36.5 (CH);
32.2; 29.7; 29.4; 29.3; 29.2; 28.9; 27.0; 26.3; 23.8; 20.5;
18.7 (CH3); 14.4 (CH3) ppm. 19F NMR (282 MHz,
CDCl3): d ꢀ 62.5 (s, 3F, –CNCF3) ppm. IR (film) m:
3005, 2929, 2856, 1590, 1461, 1379, 1331, 1285, 1155,
1119, 909, 735 cmꢀ1. MS (EI) m/z (%): 438 [(M+2)+, 1];
436 (M+, 19); 391 (36); 322 (11); 237 (49); 193 (29); 191
(39); 177 (26); 112 (30); 87 (28); 70 (100); 55 (36); 45 (37);
41 (42).
4.4.11. (R)-(ꢀ)-(Z)-1,1,1-Trifluoro-3-methyl-4-thia-13-hexa-
decen-2-one (R)-1b. A procedure identical to that de-
scribed above for (R)-1a was followed from (S,R)-8b
(35 mg, 0.08 mmol). After purification, the corresponding
trifluoromethyl ketone (R)-1b (21 mg, 81%) was obtained
20
as a colorless oil, ½aꢂD = ꢀ182.5 (c 0.95, CHCl3), ee 93%.
1H NMR (500 MHz, CDCl3): d 5.34 (m, 2H); 3.76 (q,
J = 6.9 Hz, 1H); 2.49 (dt, J1 = 12.0 Hz, J2 = 7.2 Hz, 1H);
2.32 (dt, J1 = 12.3 Hz, J2 = 7.2 Hz, 1H); 2.02 (m, 4H);
1.54 (m, 2H); 1.50 (d, J = 6.9 Hz, 3H); 1.32 (b, 10H);
0.95 (t, J = 7.5 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3):
d 185.9 (q, J = 33 Hz, COCF3); 131.6 (CH); 129.2 (CH);
115.9 (q, J = 291 Hz, COCF3); 40.9 (CH); 29.7; 29.3;
29.1; 29.0; 28.8; 28.5; 27.0; 20.5; 14.7 (CH3); 14.4 (CH3)
ppm. 19F NMR (282 MHz, CDCl3): d ꢀ74.9 (s, 3F,
–COCF3) ppm. IR (film) m: 3004, 2929, 2856, 1742, 1458,
1276, 1205, 1152 cmꢀ1. MS (EI) m/z (%): 326 [(M+2)+,
4.4.8.
azone of (Z)-1,1,1-trifluoro-3-methyl-4-thia-13-hexadecen-2-
one (R,S)-8b. A procedure identical to that described
(20R,3S)-(ꢀ)-[20-Methoxymethylpyrrolidinyl]hydr-

658
L. Mun˜oz et al. / Tetrahedron: Asymmetry 18 (2007) 651–658
1]; 324 (M+, 2); 255 (6); 229 (74); 228 (30); 227 (83); 199
(100); 155 (23); 143 (41); 141 (51); 129 (62); 123 (68); 115
(68); 109 (86); 101 (75); 95 (93); 87 (86); 81 (84); 75 (86);
69 (82); 67 (83); 55 (87); 41 (90). HRMS Calcd for
C16H27F3OS (M+): 324.1735; Found: 324.1731.
22. Riba, M.; Sans, A.; Bau, P.; Grolleau, G.; Renou, M.;
Guerrero, A. J. Chem. Ecol. 2001, 27, 1879–1897.
´
23. Riba, M.; Sans, A.; Sole, J.; Munoz, L.; Bosch, M. P.; Rosell,
˜
G.; Guerrero, A. J. Agric. Food Chem. 2005, 53, 1158–1165.
´
24. Duran, I.; Parrilla, A.; Feixas, J.; Guerrero, A. Bioorg. Med.
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´
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20
´
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Acknowledgment
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