Sulfoxide-controlled SN2′ displacements between cuprates and vinyl and alkynyl epoxy sulfoxides

Article abstract of DOI:10.1016/j.tet.2004.06.092

The S_N2′ displacement of readily available vinyl epoxy sulfoxides with organocopper reagents takes place in good yields with high anti selectivity and a good degree of E/Z stereocontrol to produce enantiopure α-hydroxy vinyl sulfoxides. A secon

Full text of DOI:10.1016/j.tet.2004.06.092

Tetrahedron 60 (2004) 8171–8180
Sulfoxide-controlled SN20 displacements between cuprates and
vinyl and alkynyl epoxy sulfoxides
*
Roberto Fernandez de la Pradilla, Alma Viso, Sonia Castro, Jorge Fernandez, Pilar Manzano
*
´
´
and Mariola Tortosa
´ ´
Instituto de Quımica Organica, CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain
Received 31 March 2004; revised 15 June 2004; accepted 17 June 2004
Available online 21 July 2004
Dedicated to the memory of Dr. Juan Carlos del Amo deceased in Madrid (11 March 2004)
Abstract—The SN20 displacement of readily available vinyl epoxy sulfoxides with organocopper reagents takes place in good yields with
high anti selectivity and a good degree of E/Z stereocontrol to produce enantiopure a-hydroxy vinyl sulfoxides. A second allylic
displacement on the related mesyloxy vinyl sulfoxides allows for the asymmetric construction of two adjacent chiral centers. In addition,
cuprate mediated SN20 addition to alkynyl epoxy sulfoxides affords a-hydroxy allenyl sulfoxides in good yields.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
subsequent synthetic manipulations of the molecules
(Scheme 1).5
Notwithstanding the advances in the past years, the
asymmetric construction of carbon–carbon bonds remains
a crucial challenge for the development of organic
synthesis. Among the existing methodology, allylic substi-
tution, namely SN20 displacement of acetates, epoxides and
other leaving groups, has been recognized as a powerful tool
in the asymmetric synthesis of a number of complex
molecules.1 Within this field and in connection with our
interest in the development of sulfur-directed method-
ology,2 previous research from our group has been focused
on the sulfoxide-controlled SN20 displacements between
cyanocuprates and mesyloxy and epoxy vinyl sulfoxides A
and B. Indeed, we have demonstrated that allylic mesylates
A, activated with a chiral sulfoxide, undergo copper
mediated SN20 displacements with high asymmetric induc-
tion and Z/E selectivity to produce enantiomerically pure
trisubstituted vinyl sulfoxides C.3 Additionally, we have
extended the scope of this methodology to enantiopure
epoxy vinyl sulfoxides B that produce densely functiona-
lised allylic alcohols D through a highly regio- and
stereoselective SN20 process.4 Moreover, further appli-
cations of these products could be envisioned due to the
presence of the vinyl sulfoxide that should allow for
To extend this study, vinyl epoxy sulfoxides E, now
available through nucleophilic epoxidation of vinyl and
dienyl sulfoxides,6 were considered. At the inception of this
research, we were aware of previous studies on the
somewhat anomalous behavior of simple sulfinyl oxiranes
Keywords: Sulfoxide; Epoxide; Cuprate; Asymmetric SN20; Allenes.
* Corresponding authors. Fax: C34-91-564-4853; e-mail addresses:
iqov379@iqog.csic.es; iqofp19@iqog.csic.es
Scheme 1.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.092

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8172
with organocuprates that rendered enolates in good yield
without incorporation of the alkyl residue on copper. At any
rate we chose to pursue this chemistry with the expectation
that an alternative reaction pathway would be operative for
our unsaturated oxiranes.7 In fact, this new class of epoxides
could undergo two consecutive asymmetric SN20 reactions.
First, allylic displacement on epoxides E would lead to
allylic alcohols F that maintain the vinyl sulfoxide group
and second, SN20 substitution on a mesylate of F would
render trisubstituted vinyl sulfoxides G with two adjacent
newly created chiral centers. In addition, we planned the
study of the nucleophilic epoxidation of sulfinyl enynes H to
produce epoxides I that incorporate an alkyne at the
electrophilic terminus8 and could lead to the asymmetric
synthesis of hydroxy sulfinyl allenes J.9 In this paper, we
present a full account of our results.
the above methodology, alkynyl vinyl sulfoxide 1g,
available from Sonogashira coupling of Z iodovinyl
sulfoxide 1f and 1-hexyne, was submitted to epoxidation
with KOOtBu and NaOOtBu. Both reagents rendered
alkynyl epoxy sulfoxides 6a and 6b with good yield,
complete regiocontrol and moderate stereoselectivity
(25:75) (Scheme 2).11–13
3. Results and discussion
To establish the experimental conditions for the allylic
displacement, we initially focused our efforts on b,trans-
oxirane 2a (Table 1). The lack of substituents at the double
bond would preclude creation of new chiral centers but also
simplify the analysis of the results. Treatment of 2a with an
excess of MeCuCNLi in Et2O rendered a highly selective
mixture of Z and E SN20 displacement products 7a and 8a
(95:2) along with a minor amount (3%) of 9a. The structure
of 9a indicated that upon quenching, protonation instead of
the slower reductive elimination was taking place at the
SN20–Cu (III) intermediate. Indeed, shortening the reaction
time [from 2 h 30 min (0 8C to rt) to 5 min (0 8C)] led to
isolation of 9a as the only product (entries 1 and 2).
2. Synthesis of starting materials
The synthesis of the enantiopure starting oxiranes was
performed through the nucleophilic epoxidation of readily
available dienyl sulfoxides with LiOOtBu and NaOOtBu.10
We have previously observed that the process takes place in
good yields, with complete regiocontrol and preservation of
the double bond geometry. Additionally, the diastereofacial
selectivity varies from moderate to excellent, depending on
the nature of the dienyl sulfoxide 1a-e and the metalated
peroxide (Li or Na).10c On the other hand, as an extension of
The influence of the stereochemistry of the epoxide ring
regarding the sulfoxide moiety was examined next.13
However, we observed that upon treatment with
MeCuCNLi a-oxirane 3a gave a non-selective mixture of
displacement products 10a and 11a along with 47% of
ketone 12 presumably derived from SN2 attack to the
epoxide (see below). The presence of a phenyl group on the
double bond, 3b (R1ZPh) increased the regioselectivity
towards SN2 attack affording exclusively ketone 13 upon
using MeCuCNLi or BuCuCNLi as nucleophiles (entries
3–5). The formation of ketones 12 and 13 (Scheme 3) can be
tentatively rationalized as an oxidative SN2 addition of the
cyanocopper reagent to give K. Rearrangement to a ketone,
followed by migration of the sulfinyl group to the adjacent
carbon and simultaneous loss of copper would lead to enone
L. Then, in situ conjugate addition of excess of MeCuCNLi
to L, followed by protonation of the enolate upon quenching
would produce 12. Alternatively, the presence of a phenyl
ring attached to the enone would prevent the second
conjugate addition affording 13.
Interestingly, the low SN20 reactivity of these a-epoxides
can be partially overcome by placing a hydroxymethyl
group at the double bond. Thus, the treatment of 3c with
MeCuCNLi afforded a moderately selective mixture of Z
and E SN20 compounds 10b, 11b and 11c (70:26:4) (entry 6)
although with a low conversion (50%).
In contrast, cis epoxides 4 and 5 display a more selective
behavior towards the SN20 addition of cyanocuprates
(entries 7–9) and we have obtained fairly selective mixtures
of SN20 products with high yields. In fact, b-epoxide 4a
underwent allylic displacement with MeCuCNLi affording
a 14:86 mixture of 10a and 11a. Additionally, treatment of
a-oxirane 5a with MeCuCNLi afforded a remarkably
selective mixture of E (8a) and Z (7a) displacement
products (94:6), along with a small amount of reduction
product 9a (16%). However, sulfinyl epoxide 5b did not
Scheme 2.

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8173
Table 1. SN20 displacements between cyanocuprates and vinyl and alkynyl epoxy sulfoxides
a
a
Z-SN20
E-SN20
Entry
Subs
Cuprate
Reduction
producta
SN2a
Allene
—
Yield (%)b
1
2a
2a
3a
3b
3b
3c
MeCuCNLic
MeCuCNLi
MeCuCNLi
MeCuCNLi
BuCuCNLi
MeCuCNLi
7a (95)
—
10a (29)
—
—
8a (2)
—
9a (3)
9a
—
—
—
—
79
45
75
76
57
31
2d
3
—
12 (47)e
13e
11a (24)
—
—
11b (26)
11c (4)
8a (79)
8b (81)
11a (86)
4
5
13e
—
6f
10b (70)
—
7
5a
5b
4a
6a,b
6a,b
MeCuCNLi
Me2CuLi
MeCuCNLi
tBuCuCNLi
nBu2CuLi
7a (5)
7b (7)
10a (14)
9a (16)
9b (12)
—
—
38
52
55
87
64
8g
9h
10i
11j
14a,b
15a,b
a
Ratios from 1H NMR spectra of the crude mixtures shown in parentheses.
b
c
d
e
f
Isolated yields for the major compound except for entries 3, 6, 10 and 11 where combined yields are given.
All experiments were conducted in Et2O.
The mixture was quenched 5 min after addition of 2a.
As a 60:40 mixture of diastereomers.
50% of starting material was recovered.
THF was used as solvent.
8% of starting material was recovered.
14 was obtained as a 39:61 mixture of diastereoisomers from a 59:41 mixture of 6a and 6b.
15 was obtained as a 37:63 mixture of diastereoisomers from a 34:66 mixture of 6a and 6b.
g
h
i
j
react with MeCuCNLi leading to starting material exclu-
sively. At this point we explored different reaction conditions
and found that 5b behaved similarly to 5a upon treatment with
Gilman’s cuprate (Me2CuLi) affording a good selectivity of
SN20 products (8b/7b, 92:8) and a 12% of 9b.
Finally, we briefly explored the reactivity of alkynyl epoxy
sulfoxides 6a and 6b towards organocopper reagents (Table
t
1, entries 10 and 11). Addition of BuCNCuLi to a 59:41
mixture of epoxides led to a diasteromeric mixture (39:61)
of hydroxy allenyl sulfoxides 14a,b with good yield (87%).
Seeking to improve this result the addition of homocuprate,
nBu2CuLi, was also carried out and a 37:63 mixture of
allenes 15a,b was obtained. These initial results outline the
potential versatility of our methodology to produce highly
functionalized enantiopure allenes.14
To understand the stereochemical outcome of the SN20
Scheme 3.

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8174
(2a, R1ZH, see scheme of Table 1) excluded the formation
of two consecutive chiral centers, a high degree of
diastereocontrol was observed for (Z)-a-mesyloxy vinyl
sulfoxides 7a. Thus, this result complements our previous
studies of the SN20 displacements of (E)-a-mesyloxy vinyl
sulfoxides.
Subsequently, compound 8b was selectively protected at the
primary alcohol to give 8c and then was mesylated at the
secondary alcohol under standard conditions to render 8d.
The SN20 addition of MeCuCNLi to allylic mesylate 8c
proceeds with high regio- and stereocontrol affording a 91:9
mixture of displacement products 17a and 17b. Tentative
structural assignment of the products was based on an anti
attack of the cuprate to the mesylate. Additionally, the
Scheme 4.
process we have considered that the major product from cis
epoxides, [a-(5a,b) and b-(4a)], has an E stereochemistry
(8a, 8b and 11a) and from trans epoxide [b-(2a) and a-(3c)]
a Z vinyl sulfoxide was obtained (7a, 10b). These results
indicate that for cis and trans epoxides a different reactive
conformation, s-cis or s-trans, is operative in these
processes (Scheme 4). Indeed, for trans epoxides the
arrangement of the butyl group would preclude the s-cis
conformation leading to Z stereochemistry in the displace-
ment products.15 On the other hand, through an inspection
of the NMR data of related vinyl sulfoxides, we have
tentatively determined that addition of the cyanocuprate to
vinyl epoxy sulfoxide 5b occurs with anti stereochemistry
for the major product 8b.16
1
comparison with the H NMR data of related SN20
compounds allowed to establish tentatively the structure
of the new trisubstituted vinyl sulfoxides.16,18
In summary, we have demonstrated that SN20 displacements
of readily available vinyl epoxy sulfoxides using organo-
copper reagents as nucleophiles occur with high anti
selectivity and a good degree of E/Z stereocontrol to
produce enantiopure a-hydroxy vinyl sulfoxides in good
yields. A subsequent allylic displacement on the related
mesyloxy vinyl sulfoxides allows for the asymmetric
construction of two adjacent chiral centers in the molecules.
In addition, we have briefly explored the cuprate mediated
SN20 addition to alkynyl epoxy sulfoxides that leads to a-
hydroxy allenyl sulfoxides in good yield. However, the
future studies and applications of this methodology would
require the development of alternative routes to alkynyl
oxiranes.
To extend the scope of our methodology we undertook the
study of the second SN20 displacement on allylic mesylates
derived from 7a and 8b. This process would allow for the
asymmetric construction of two adjacent chiral centers
through two consecutive copper-mediated SN20 displace-
ments (Scheme 5). Therefore, a-hydroxy vinyl sulfoxide 7a
was reacted with mesyl chloride and Et3N affording a good
yield of 7c, that upon treatment with MeCuCNLi gave a
mixture of displacement products 16a17 and 16b with high
diastereoselectivity (93:7). Although the absence of substi-
tution at the double bond of the precursor epoxy sulfoxide
4. Experimental
4.1. General
Reagents and solvents were handled by using standard
syringe techniques. All reactions were carried out under an
argon atmosphere. Hexane, toluene and CH2Cl2 were
distilled from CaH2, and THF and Et2O from sodium.
(MeO)2P(O)Me, Et3N, i-Pr2NH, i-Pr2EtN, t-BuMe2SiOTf
were distilled from CaH2. Crude products were purified by
flash chromatography on Merck 230–400 mesh silica gel
with distilled solvents. Analytical TLC was carried out on
Merck (Kieselgel 60F-254) silica gel plates with detection
by UV light, iodine, acidic vanillin solution, 10%
phosphomolybdic acid solution in ethanol. All reagents
were commercial products purchased from Aldrich, Acros,
Fluka or Merck. Organolithium reagents were titrated prior
to use by reacting with 3,4-dimethoxybenzaldehyde. NaH
and KH (60% in mineral oil) were washed repeatedly with
dry hexane and dried prior to use. Through this section, the
volume of solvents is reported in mL/mmol of starting
material. Infrared spectra (IR) were obtained on a Perkin–
Elmer 681 and on a Perkin–Elmer Spectrum one. 1H and 13
C
NMR spectra were recorded on a Bru¨ker AM-200
(200 MHz), Varian Gemini-200 (200 MHz), Varian
INOVA-300 (300 MHz) and Varian INOVA-400
(400 MHz) using CDCl3 as solvent and with the residual
solvent signal as internal reference (CDCl3, 7.24 and
Scheme 5.

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R. Fernandez de la Pradilla et al. / Tetrahedron 60 (2004) 8171–8180
8175
77.0 ppm). The following abbreviations are used to describe
peak patterns when appropriate: s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), br (broad). Melting
points were determined on a Reichert Kofler microscope
and are uncorrected. Optical rotations were measured on a
Perkin–Elmer 241 polarimeter at 20 8C using a sodium lamp
and in CHCl3 solution. Low resolution mass spectra were
recorded by direct injection on a Hewlett–Packard 5973
MSD instrument using the electronic impact technique with
an ionizacion energy of 70 eV or on a Hewlett–Packard
1100 MSD instrument using the atmospheric pressure
chemical ionizacion (APCI) or electrospray (ES) chemical
ionizacion techniques in its positive or negative modes.
High resolution mass spectra (HRMS) were obtained on a
VG-250-S spectrometer or on a Finnigan-4201 spectro-
meter. Elemental analyses were carried out on a Perkin–
Elmer 240C and on a Heraus CHN-O-Rapid instruments at
oil. Due to unstability of the samples rapid manipulation of
the products and storage in benzene at K17 8C was
necessary. A similar result was obtained from NaH
(33 mg, 1.36 mmol) in 7.0 mL of THF, t-BuOOH
(0.17 mL, 122 mg, 1.35 mmol) and a solution of 1g
(103 mg, 0.34 mmol) in 2.5 mL of THF at 0 8C (1 h
10 min). After chromatography (0–5% Et2O–CH2Cl2) was
isolated 6a (14 mg, 13%), 6b (31 mg, 29%) and a mixture of
both epoxides (32 mg, 30%).
Data for 6a. RfZ0.26 (CHCl3). 1H NMR (200 MHz) d 0.82
(t, 3H, JZ7.1 Hz, Me n-Bu), 0.94 (t, 3H, JZ7.1 Hz, Me
n-Bu), 1.17–1.65 (m, 8H), 1.95–2.19 (m, 4H), 2.40 (s, 3H,
Me p-Tol), 3.48 (dd, 1H, JZ6.8, 5.7 Hz, H-3), 7.30 (d, 2H,
JZ7.9 Hz, ArH), 7.57 (d, 2H, JZ8.2 Hz, ArH). 13C NMR
(50 MHz) d 13.5 (Me n-Bu), 13.9 (Me n-Bu), 18.6, 21.5 (Me
p-Tol), 210.7, 22.4, 27.7, 28.3, 30.0, 67.5 (C-3), 70.1, 70.2,
92.0 (C-2 alkyne), 125.2 (2C p-Tol), 129.3 (2C p-Tol),
136.8, 142.0. IR (CHCl3): 3010, 2980, 2920, 2380, 1620,
1515, 1490, 1400, 1115, 830 cmK1. MS (APCI): 319 [MC
1]C.
´ ´
Instituto de Quımica Organica, CSIC (Madrid).
4.2. Preparation of starting materials
Vinyl epoxy sulfoxides 2a, 3a-c, 4a and 5a,b were prepared
Data for 6b. RfZ0.19 (CHCl3). 1H NMR (200 MHz) d 0.82
(t, 3H, JZ7.2 Hz, Me n-Bu), 0.93 (t, 3H, JZ7.2 Hz, Me
n-Bu), 1.15–1.59 (m, 8H), 1.90–2.02 (m, 2H), 2.13 (t, 2H,
JZ6.8 Hz, 2H-10 n-Bu), 2.41 (s, 3H, Me p-Tol), 3.34 (m,
1H-3), 7.31 (d, 2H, JZ7.9 Hz, ArH), 7.59 (d, 2H, JZ
8.2 Hz, ArH). 13C NMR (50 MHz) d 13.5 (Me n-Bu), 13.9
(Me n-Bu), 18.5, 21.5 (Me p-Tol), 210.7, 22.2, 27.7, 28.9,
29.9, 66.8 (C-3), 71.0, 71.8, 92.0 (C-2 alkyne), 125.5 (2C
p-Tol), 129.5 (2C p-Tol), 138.0, 142.3. MS (APCI): 319
[MC1]C.
according to procedures previously reported by us.10
4.2.1. Synthesis of (G)-6-(p-tolylsulfinyl)-dodec-5-en-7-
yne, 1g. To a solution of 1f17 (642 mg, 1.84 mmol) in
benzene (18 mL) at room temperature was added CuI
(105 mg, 0.552 mmol), DBU (1,8-diazabicyclo[5.4.0.]-
undec-7-ene) (0.55 mL, 561 mg, 3.68 mmol), 1-hexyne
(0.63 mL, 450 mg, 5.48 mmol) and Pd(Ph3P)4 (106 mg,
0.092 mmol). After 45 min the mixture was quenched with a
saturated solution of NH4Cl (5 mL/mmol) and H2O (5 mL/
mmol), and extracted with EtOAc (3!3 mL/mmol). The
organic layer was washed with brine (2!4 mL/mmol) dried
over anhydrous MgSO4 and evaporated to afford a crude
product that was purified by chromatography on silica gel
(0–30% EtOAc–hexane). Pure 1g was obtained (377 mg,
68%) as a yellow oil and was stored in benzene at K17 8C
due to unstability of the samples
4.3. General procedure for the SN20 displacement with
cuprates
Argon was bubbled to a suspension of 3–6 equiv. of CuCN
or CuI in Et2O (10 mL!mmol) during 10 min (occasionally
THF was employed as solvent). Then, the mixture was
cooled to 0 8C and 3–6 equiv. of MeLi or n-BuLi was added.
After 10 min stirring, 1 equiv. of sulfinyl oxirane in Et2O
(10 mL!mmol) was added dropwise and the yellow
solution turned colorless. The reaction mixture was stirred
at 0 8C for 30 min and then at room temperature (2–18 h)
approximately turning from colorless to black. Then the
reaction was quenched with a saturated solution of Na2S2O4
(4 mL!mmol) and diluted with EtOAc (8 mL!mmol).
The aqueous layer was extracted with EtOAc (3!10 mL!
mmol) and the organic extracts were washed with brine
(4 mL!mmol), dried over anhydrous MgSO4 and evapo-
rated under vacuum. Chromatography on silica gel using
mixtures of EtOAc–hexane as eluent afforded pure
displacement products. The ratio of isomers was measured
by integration of well resolved peaks of the crude 1H NMR
spectra.
Data for 1g. RfZ0.22 (20% EtOAc–hexane). 1H NMR
(200 MHz) d 0.80 (t, 3H, JZ7.1 Hz, Me n-Bu), 0.92 (t, 3H,
JZ7.1 Hz, Me n-Bu), 1.11–1.49 (m, 8H), 2.21 (t, 2H, JZ
6.8 Hz, H-9), 2.37 (s, 3H, Me p-Tol), 2.45–2.80 (m, 2H,
H-4), 6.32 (dd, 1H, JZ8.4, 7.7 Hz, H-5), 7.26 (d, 2H, JZ
7.9 Hz, ArH), 7.47 (d, 2H, JZ8.2 Hz, ArH). 13C NMR
(50 MHz) d 13.5 (Me n-Bu), 13.8 (Me n-Bu), 19.0, 21.4 (Me
p-Tol), 21.7, 22.2, 28.7, 30.3, 31.2, 72.1 (C-7), 96.1 (C-8),
124.5 (2C p-Tol), 129.4 (2C p-Tol), 132.9, 139.9, 141.0,
145.2 (C-5). IR (film): 2965, 2940, 2300, 1595, 1485, 1460,
1445, 1075, 1050, 795 cmK1. MS (APCI): 303 [MC1]C
(100%).
4.2.2. Synthesis of (G)-(2S,3R,SS)-3-n-butyl-2-(10-hexy-
nyl)-2-(p-tolylsulfinyl)oxirane, 6a and (G)-(2R,3S,SS)-3-
n-butyl-2-(10-hexynyl)-2-(p-tolylsulfinyl)oxirane, 6b. From
KH (24 mg, 0.60 mmol), t-BuOOH (75 mL, 54 mg,
0.60 mmol) in THF (3.0 mL) and a solution of 1g (45 mg,
0.15 mmol) in 1.1 mL of THF, from K30 to K15 8C
(35 min) following the method reported by us10 was
obtained a 25:75 mixture of 6a and 6b. Purification by
chromatography on silica gel (0–60% EtOAc–CH2Cl2)
yielded 43 mg (90%) of the mixture of epoxides as a yellow
4.3.1. Synthesis of (K)-(5S,SS)-(3Z)-4-(p-tolylsulfinyl)-
non-3-en-5-ol, 7a, (K)-(5S,SS)-(3E)-4-(p-tolylsulfinyl)-
non-3-en-5-ol, 8a and (K)-(4S,SS)-(2E)-3-(p-tolylsulfinyl)-
oct-2-en-4-ol, 9a. From CuCN (60.5 mg, 0.675 mmol) in
6.7 mL of Et2O, MeLi (0.42 mL, 1.6 M, 0.675 mmol) and
2a (59.5 mg, 0.225 mmol) in 2.2 mL of Et2O following the
above procedure (2 h) was obtained a mixture of 7a, 8a and

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8176
9a (95:2:3). After chromatography (20–50% EtOAc–
hexane) 50 mg (79%) of 7a was isolated as a pale yellow
oil. When the reaction was quenched after 5 min at 0 8C
[CuCN (19 mg, 0.21 mmol), MeLi (0.15 mL, 1.4 M,
0.21 mmol), 2a (11 mg, 0.04 mmol)] was obtained 9a as a
single product (4.9 mg, 45%).
123, 108, 91, 81. HRMS calcd for C16H25O2S [MC1]C:
281.1575. Found: 281.1562. Anal. calcd for C16H24O2S: C,
68.53; H, 8.63; S, 11.43. Found: C, 68.74; H, 8.78; S, 11.18.
4.3.3. Synthesis of (C)-(5R,SS)-(3E)-4-(p-tolylsulfinyl)-
non-3-en-5-ol, 11a. From CuCN (20 mg, 0.22 mmol) in
2.2 mL of Et2O, MeLi (0.16 mL, 1.4 M, 0.22 mmol) and 4a
(19.7 mg, 0.074 mmol) in 0.7 mL of Et2O following the
above procedure (2 h) was obtained a mixture of 4a, 11a and
10a (8:79:13). After chromatography (20–50% EtOAc–
hexane) 11.4 mg (55%) of pure 11a was isolated as a
colorless oil.
Data for 7a. RfZ0.14 (30% EtOAc–hexane). [a]2D0Z
1
K181.1 (cZ1.03). H NMR (300 MHz) d 0.72 (t, 3H, JZ
6.6 Hz, Me), 0.95–1.20 (m, 4H, H-7, H-8), 1.14 (t, 3H, JZ
7.4 Hz, Me), 1.23–1.32 (m, 1H, H-6), 1.50–1.60 (m, 1H,
H-6), 2.38 (s, 3H, Me p-Tol), 2.48 (m, 1H, H-2), 2.71 (m,
1H, H-2), 3.53 (d, 1H, JZ2.3 Hz, OH), 4.28 (ap td, 1H, JZ
7.8, 2.2 Hz, H-5), 6.17 (dd, 1H, JZ8.2, 7.0 Hz, H-3), 7.28
(d, 2H, JZ8.2 Hz, ArH), 7.41 (d, 2H, JZ8.3 Hz, ArH). 13C
NMR (50 MHz) d 13.7 (Me), 13.8 (Me), 21.2 (Me p-Tol),
22.1, 22.3, 27.5, 34.1 (C-2), 67.2 (C-5), 124.1 (2C p-Tol),
129.8 (2C p-Tol), 138.9 (2C), 140.9, 144.9. IR (film): 3400
(br), 2960, 2940, 2880, 1650, 1600, 1500, 1460, 1380, 1120,
1090, 1050, 1020, 810 cmK1. MS (CI/CH4): 282 [MC2]C,
281 [MC1]C (100%), 263, 247, 139, 123. HRMS calcd for
C16H25O2S [MC1]C: 281.1575. Found: 281.1570.
Data for 11a. RfZ0.15 (30% EtOAc–hexane). [a]2D0Z
1
C23.2 (cZ1.09). H NMR (200 MHz) d 0.77 (t, 3H, JZ
7.3 Hz, Me), 1.10 (t, 3H, JZ7.5 Hz, Me), 1.11–1.64 (m, 6H,
H-6, H-7, H-8), 2.33 (m, 2H, H-2), 2.38 (s, 3H, Me p-Tol),
2.53 (br s, 1H, OH), 4.53 (m, 1H, H-5), 6.43 (t, 1H, JZ
7.6 Hz, H-3), 7.28 (d, 2H, JZ8.9 Hz, ArH), 7.52 (d, 2H, JZ
8.3 Hz, ArH). 13C NMR (50 MHz) d 13.5 (Me), 13.8 (Me),
21.3 (Me p-Tol), 21.9, 22.3, 27.9, 36.6 (C-2), 70.2 (C-5),
125.0 (2C p-Tol), 129.8 (2C p-Tol), 139.3, 140.7, 141.2,
144.8. IR (film): 3400 (br), 2980, 2960, 2880, 1650, 1600,
1500, 1460, 1380, 1090, 1040, 810 cmK1. MS (CI/NH3):
292 [MCNH4]C, 281 [MC1]C (100%), 263, 247, 223,
195, 165, 140, 123. HRMS calcd for C16H25O2S [MC1]C:
281.1575. Found: 282.1566.
Data for 9a. RfZ0.10 (30% EtOAc–hexane). [a]2D0ZK16.9
1
(cZ0.80). H NMR (500 MHz) d 0.85 (t, 3H, JZ6.7 Hz,
Me n-Bu), 1.18–1.28 (m, 4H, H-6, H-7), 1.53–1.59 (m, 2H,
H-5), 1.92 (d, 3H, JZ7.2 Hz, H-1), 2.36 (s, 3H, Me p-Tol),
2.36–2.38 (m, 1H, OH), 4.42–4.45 (m, 1H, H-4), 6.37 (q,
1H, JZ7.2 Hz, H-2), 7.25 (d, 2H, JZ7.9 Hz, ArH), 7.47 (d,
2H, JZ8.3 Hz, ArH). DNOE between Me vinyl/H-2: 9%;
between Me vinyl/H-4: 3%; between H-2/Me vinyl: 3.3%;
between H-2/ArH: 1.2%; between H-4/Me vinyl: 1.7%;
between H-4/ArH: 1.1%. 13C NMR (50 MHz) d 13.8 (Me
n-Bu), 14.5, 21.3, 22.2, 28.0, 36.6 (C-1), 68.8 (C-4), 125.3
(2C p-Tol), 129.8 (2C p-Tol), 131.9 (2C), 141.4, 147.6. IR
(film): 3400 (br), 2980, 2970, 2940, 2870, 1600, 1500, 1460,
1380, 1120, 1090, 1050, 1020, 810 cmK1. MS (CI/CH4):
268, 267 [MC1]C (100%), 249, 233, 109. HRMS calcd for
C15H23O2S [MC1]C: 267.1419. Found: 267.1417. Anal.
calcd for C15H22O2S: C, 67.39;H, 8.20; S, 11.96. Found: C,
67.52;H, 8.05; S, 11.87.
Partial data for 10a from the mixture. 1H NMR (200 MHz):
d 4.35 (m, 1H, H-5), 6.21 (dd, 1H, JZ8.2, 7.0 Hz, H-3).
4.3.4. Synthesis of (K)-(5R,SS)-(3Z)-4-(p-tolylsulfinyl)-
non-3-en-5-ol, 10a, and (C)-(5R,SS)-(3E)-4-(p-tolylsul-
finyl)-non-3-en-5-ol, 11a, and 5-(p-tolylsulfinyl)-non-4-
one, 12. From CuCN (25 mg, 0.28 mmol) in 20.75 mL of
Et2O, MeLi (0.17 mL, 0.27 mmol) and 3a (17 mg,
0.064 mmol) in 0.50 mL of Et2O following the above
procedure (2 h) was obtained a mixture of 10a, 11a and 12
(29:24:47). After chromatography (5–40% EtOAc–hexane)
3 mg (23%) of pure 10a, 2 mg (16%) of pure 11a and 9 mg
(36%) of 12 as a 60:40 mixture of diastereoisomers was
isolated. Data for isolated 11a are the same as above.
4.3.2. Synthesis of (K)-(5S,SS)-(3E)-4-(p-tolylsulfinyl)-
non-3-en-5-ol, 8a. From CuCN (17.3 mg, 0.20 mmol) in
2 mL of Et2O, MeLi (0.14 mL, 1.4 M, 0.20 mmol) and
5a (17 mg, 0.064 mmol) in 0.6 mL of Et2O following the
above procedure (2 h) was obtained a mixture of 7a, 8a and
9a (5:79:16). After chromatography (20–50% EtOAc–
hexane) 7 mg (38%) of pure 8a was isolated as a colorless
oil.
Data for 10a. RfZ0.18 (30% EtOAc–hexane). [a]2D0Z
K108.8 (cZ1.25). H NMR (300 MHz) d 0.81 (t, 3H, JZ
1
7.1 Hz, Me n-Bu), 1.12 (t, 3H, JZ7.4 Hz, Me Et), 1.10–1-
38 (m, 4H, H-7, H-8), 1.52–1.61 (m, 2H, H-6), 2.24 (d, 1H,
JZ5.1 Hz, OH), 2.34–2.48 (m, 1H, H-2), 2.38 (s, 3H, Me
p-Tol), 2.58–2.71 (m, 1H, H-2), 4.36 (ap q, 1H, JZ6.5 Hz,
H-5), 6.22 (dd, 1H, JZ8.6, 6.8 Hz, H-3), 7.29 (d, 2H, JZ
8.1 Hz, ArH), 7.48 (d, 2H, JZ8.3 Hz, ArH). IR (CCl4):
3400 (br), 2960, 2930, 2860, 1740, 1640, 1600, 1495, 1460,
1380, 1260, 1080, 1030, 1015, 810 cmK1. MS (EI): 281
(MC1), 263, 245, 223, 193, 149, 140 (100%), 139, 123,
111, 95, 92, 91, 81, 69, 57, 43, 41.
Data for 8a. RfZ0.13 (30% EtOAc–hexane). [a]2D0ZK25.5
1
(cZ0.64). H NMR (200 MHz) d 0.74 (t, 3H, JZ7.0 Hz,
Me), 1.08 (t, 3H, JZ7.5 Hz, Me), 1.09–1.33 (m, 5H), 1.47–
1.63 (m, 1H), 2.25–2.42 (m, 2H), 2.38 (s, 3H, Me p-Tol),
2.47 (d, 1H, JZ5.3 Hz, OH), 4.42 (m, 1H, H-5), 6.28 (t, 1H,
JZ7.6 Hz, H-3), 7.27 (d, 2H, JZ8.1 Hz, ArH), 7.49 (d, 2H,
JZ8.2 Hz, ArH). 13C NMR (50 MHz) d 13.5 (Me), 13.8
(Me), 21.3 (Me p-Tol), 22.1 (2C), 28.1, 37.0 (C-2), 68.9
(C-5), 125.3 (2C p-Tol), 129.8 (2C p-Tol), 138.6, 140.3,
141.4, 146.3. IR (film): 3400, 2980, 2960, 2940, 1600, 1490,
1460, 1380, 1090, 1040, 1010, 810 cmK1. MS (CI/NH3):
281 [MC1]C, 265 (100%), 247, 233, 224, 195, 158, 141,
Partial data for 12 (major isomer, from the mixture). RfZ
0.26 (30% EtOAc–hexane). 1H NMR (300 MHz) d 2.39 (s,
3H, Me p-Tol), 3.54 (dd, JZ9.9, 4.9 Hz, H-5).
Partial data for 12 (minor isomer, from the mixture). RfZ
0.26 (30% EtOAc–hexane). 1H NMR (300 MHz) d 2.40 (s,
3H, Me p-Tol), 3.67 (dd, JZ9.6, 4.6 Hz, H-5).

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R. Fernandez de la Pradilla et al. / Tetrahedron 60 (2004) 8171–8180
8177
4.3.5. Synthesis of (E)-1-phenyl-4-(p-tolylsulfinyl)-1-en-
3-octanone, 13. From CuCN (16 mg, 0.18 mmol) in 0.4 mL
of Et2O, MeLi (0.11 mL, 0.18 mmol) and 3b (10 mg,
0.03 mmol) in 0.3 mL of Et2O following the above
procedure (18 h) was obtained after chromatography
(5–30% EtOAc–hexane) 8 mg (76%) of 13 as a 60:40
inseparable mixture of diastereomers. Alternatively, using
n-BuLi (0.16 mL, 0.18 mmol) instead of MeLi and follow-
ing the same procedure (5 h) was obtained after chroma-
tography (5–30% EtOAc–hexane) 6 mg (57%) of 13 as a
60:40 mixture of diastereomers.
4.3.7. Synthesis of (C)-(2R,5S,SS)-(3E)-2-methyl-4-(p-
tolylsulfinyl)-non-3-en-1,5-diol, 8b, (2S,5S,SS)-(3Z)-2-
methyl-4-(p-tolylsulfinyl)-non-3-en-1,5-diol, 7b and
(5S,SS)-(3E)-4-(p-tolylsulfinyl)-non-3-en-1,5-diol, 9b.
From CuI (288 mg, 1.51 mmol) in 3.75 mL of THF, MeLi
(1.86 mL, 2.98 mmol) and 5b (73 mg, 0.25 mmol) in
2.5 mL of THF following the above procedure (18 h) was
obtained a mixture of 8b, 7b, and 9b (81:7:12). After
chromatography (20–100% EtOAc–hexane) was isolated
40 mg (52%) of 8b, 3 mg (4%) of 7b and 6 mg (8%) of 9b as
colorless oils.
Data for 13 (major, from the mixture). RfZ0.37 (30%
EtOAc–hexane). H NMR (300 MHz) d 0.86 (m, 3H, Me
Data for 8b. RfZ0.09 (EtOAc). [a]2D0ZC84.6 (cZ2.0). 1H
NMR (300 MHz) d 0.73 (t, 3H, JZ7.0 Hz, Me n-Bu), 1.03
(d, 3H, JZ6.7 Hz, Me), 1.05–1.66 (m, 6H, H-6, H-7, H-8),
2.38 (s, 3H, Me p-Tol), 2.93–3.00 (m, 1H, H-2), 3.22 (br s,
1H, OH), 3.45 (dd, 1H, JZ10.4, 8.8 Hz, H-1), 3.62 (dd, 1H,
JZ10.6, 5.0 Hz, H-1), 4.56 (dd, 1H, JZ8.9, 4.7 Hz, H-5),
6.15 (d, 1H, JZ10.6 Hz, H-3), 7.26 (d, 2H, JZ8.1 Hz,
ArH), 7.52 (d, 2H, JZ8.2 Hz, ArH). DNOE between H-2/
Me: 3.5%; between H-2/H-5: 5.9%; between Me/H-2: 1.7%;
between Me/H-3: 1.3%; between H-5/H-2: 8.0%; between
H-5/Me: 2.7%. 13C NMR (50 MHz) d 13.7 (Me), 16.3 (Me),
21.4 (Me p-Tol), 22.2, 27.9, 35.6, 36.0, 66.8, 68.5, 126.1,
128.3 (2C p-Tol), 129.8 (2C p-Tol), 141.9, 147.9, 148.6. IR
(CHCl3): 3400 (br), 2960, 2930, 2870, 1600, 1395, 1460,
1380, 1305, 1215, 1080, 1030, 1010, 790, 760 cmK1. MS
(EI): 293, 253, 171, 153, 140, 139, 97, 95, 92, 71, 57, 55, 41
(100%).
1
n-Bu), 1.31 (m, 2H), 1.52–1.60 (m, 2H), 2.05–2.13 (m, 2H),
2.26 (s, 3H, Me p-Tol), 3.97 (dd, 1H, JZ9.9, 4.5 Hz, H-4),
6.49 (d, 1H, JZ16.9 Hz, H-2), 7.16–7.49 (m, 10H, Ph,
p-Tol and H-1). IR (CCl4, mixture of isomers): 2960, 2930,
2860, 1680, 1650, 1610, 1580, 1495, 1450, 1345, 1080,
1050, 990, 975 cmK1
.
Data for 13 (minor, from the mixture). RfZ0.37 (30%
EtOAc–hexane). H NMR (300 MHz) d 0.86 (m, 3H, Me
1
n-Bu), 1.31 (m, 2H), 1.93–1.96 (m, 2H), 2.28–2.40 (m, 2H),
2.32 (s, 3H, Me p-Tol), 3.81 (dd, 1H, JZ8.3, 6.2 Hz, H-4),
6.73 (d, 1H, JZ16.0 Hz, H-2), 7.16–7.49 (m, 10H, Ph,
p-Tol and H-1).
4.3.6. Synthesis of (K)-(2S,5R,SS)-(3Z)-2-methyl-4-(p-
tolylsulfinyl)-non-3-en-1,5-diol, 10b and (2S,5R,SS)-
(3E)-2-methyl-4-(p-tolylsulfinyl)-non-3-en-1,5-diol, 11b.
From CuCN (27 mg, 0.30 mmol) in 0.75 mL of Et2O,
MeLi (0.18 mL, 0.29 mmol) and 3b (14 mg, 0.05 mmol) in
0.5 mL of Et2O following the above procedure (4 h)
was obtained a mixture of 10b, 11b, and 11c (70:26:4).
After chromatography (20–100% EtOAc–hexane) was
isolated 16 mg (22%) of 10b and 7 mg (9%) of 11b as
colorless oils.
Partial data for 7b. RfZ0.12 (EtOAc). 1H NMR (300 MHz)
d 1.11 (d, 3H, JZ6.5 Hz, Me), 2.38 (s, 3H, Me p-Tol), 3.52
(m, 1H, H-2), 3.71 (dd, 1H, JZ10.1, 5.1 Hz, H-1), 4.01 (dd,
1H, JZ12.3, 4.8 Hz, H-1), 4.26 (dd, 1H, JZ8.0, 5.7 Hz,
H-5), 6.05 (d, 1H, JZ10.1 Hz, H-3), 7.22–7.60 (m, 4H,
ArH).
Partial data for 9b. RfZ0.05 (EtOAc). 1H NMR (200 MHz)
d 0.66 (t, 3H, JZ7.0 Hz, Me n-Bu), 2.37 (s, 3H, Me p-Tol),
3.81 (t, 2H, JZ5.6 Hz, H-1), 4.41 (dd, 1H, JZ8.9, 4.4 Hz,
H-5), 6.51 (t, 1H, JZ7.4 Hz, H-3), 7.26 (d, 2H, JZ8.0 Hz,
ArH), 7.48 (d, 2H, JZ8.2 Hz, ArH).
Data for 10b. RfZ0.27 (75% EtOAc–hexane). [a]2D0Z
1
K23.6 (cZ0.36). H NMR (300 MHz) d 0.84 (t, 3H, JZ
7.0 Hz, Me n-Bu), 1.03 (d, 3H, JZ6.4 Hz, Me), 1.15–1.39
(m, 4H), 1.56–1.67 (m, 2H), 2.03 (br s, 1H, OH), 2.16 (br s,
1H, OH), 2.38 (s, 3H, Me p-Tol), 3.37–3.48 (m, 2H, H-1),
3.69 (m, 1H, H-2), 4.30 (t, 1H, JZ6.6 Hz, H-5), 6.07 (d, 1H,
JZ10.3 Hz, H-3), 7.28 (d, 2H, JZ8.0 Hz, ArH), 7.64 (d,
2H, JZ8.3 Hz, ArH). 13C NMR (50 MHz) d 13.9 (Me), 16.7
(Me), 21.2 (Me p-Tol), 22.4, 27.8, 35.8, 37.3, 67.1, 69.8,
124.9, 126.6 (2C p-Tol), 129.9 (2C p-Tol), 142.1, 147.5,
147.9. MS (EI): 293, 259, 253, 223, 205, 177, 169, 153, 140,
139, 97, 95, 92, 69, 57, 43 (100%).
4.3.8. Synthesis of (G)-(5R,7R,SS)-8-tert-butyl-6-(p-tolyl-
sulfinyl)-dodeca-6,7-dien-5-ol, 14a and (G)-(5S,7S,SS)-8-
tert-butyl-6-(p-tolylsulfinyl)-dodeca-6,7-dien-5-ol, 14b.
From CuCN (29 mg, 0.32 mmol) in 2.6 mL of THF,
t-BuLi (1.5 M, 0.21 mL, 0.31 mmol) and a mixture of
sulfinyl oxiranes 6a and 6b 41:59 (25 mg, 0.79 mmol) in
0.4 mL of THF following the above procedure (5 min at
K78 8C and 30 min at rt) was obtained a mixture of 14a and
14b (39:61). After chromatography (0–30% EtOAc–
CH2Cl2) was isolated 26 mg (87%) of the mixture of
allenes as a colorless oil. Pure compounds were isolated by
preparative TLC (3% MeOH–toluene).
1
Data for 11b. RfZ0.24 (75% EtOAc–hexane). H NMR
(300 MHz) d 0.79 (t, 3H, JZ6.6 Hz Me n-Bu), 0.90 (d, 3H,
JZ6.8 Hz, Me), 1.09–1.36 (m, 4H), 1.61–1.80 (m, 2H),
2.07 (br s, 1H, OH), 2.33 (br s, 1H, OH), 2.40 (s, 3H, Me
p-Tol), 3.16–3.37 (m, 2H, H-1), 3.40–3.69 (m, 1H, H-2),
4.19 (dd, 1H, JZ9.3, 3.5 Hz, H-5), 6.24 (d, 1H, JZ10.7 Hz,
H-3), 7.26–7.57 (m, 4H, ArH).
Data for 14a. RfZ0.13 (3% MeOH–toluene). 1H NMR
(300 MHz) d 0.77 (t, 3H, JZ6.9 Hz, Me n-Bu), 0.88 (t, 3H,
JZ7.2 Hz, Me n-Bu), 1.14 (s, 9H, 3Me t-Bu), 1.05–1.47 (m,
10H), 2.03 (t, 2H, JZ7.9 Hz), 2.40 (s, 3H, Me p-Tol), 3.75
(br s, 1H, OH), 4.30 (dd, 1H, JZ7.3, 5.9 Hz, H-5), 7.30 (d,
2H, JZ7.9 Hz, ArH), 7.53 (d, 2H, JZ8.2 Hz, ArH). 13C
NMR (50 MHz) d 13.9 (Me n-Bu), 14.0 (Me n-Bu), 21.4
Partial data of 11c (from the mixture). RfZ0.24 (75%
EtOAc–hexane). 1H NMR (300 MHz) d 4.58 (m, 1H, H-5),
6.36 (d, 1H, JZ10.5 Hz, H-5).

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R. Fernandez de la Pradilla et al. / Tetrahedron 60 (2004) 8171–8180
8178
(Me p-Tol), 22.4, 22.7, 27.4, 27.6, 29.2 (3Me t-Bu), 30.8,
34.9, 35.0, 68.6 (C-5), 124.4, 124.6 (2C p-Tol), 125.4, 129.7
(2C p-Tol), 139.6, 141.4, 197.9 (C-7). IR (CHCl3): 3370,
H-3), 7.28 (d, 2H, JZ8.4 Hz, ArH), 7.38 (d, 2H, JZ8.3 Hz,
ArH).
2960, 2884, 1930, 1585, 1483, 1460, 1230, 1021, 799 cmK1
.
4.3.11. Synthesis of (C)-(3R,SS)-(4E)-3-methyl-4-(p-
tolylsulfinyl)-non-4-ene, 16a. From CuCN (52 mg,
0.58 mmol) in 5.8 mL of THF, MeLi (0.36 mL, 1.6 M,
0.58 mmol) and mesylate 7c (67 mg, 0.19 mmol) in 2 mL of
THF following the above procedure (1 h at K78 8C) was
obtained a mixture of 16a and 16b (93:7). After chroma-
tography (20–50% EtOAc–hexane) was isolated 35 mg
(71% from 7a) of 16a as a colorless oil.
MS (ES): 775 [2MCNa]C, 399 [MCNa]C (100%), 377
[MC1]C.
Data for 14b. RfZ0.09 (3% MeOH–toluene). 1H NMR
(300 MHz) d 0.89 (s, 9H, 3Me t-Bu), 0.84–0.92 (m, 6H,
2Me n-Bu), 1.22–1.39 (m, 8H), 1.46–1.66 (m, 2H), 1.88–
2.15 (m, 2H), 2.40 (s, 3H, Me p-Tol), 2.75 (br s, 1H, OH),
4.52 (br t, 1H, JZ6.4 Hz, H-5), 7.28 (d, 2H, JZ7.8 Hz,
ArH), 7.55 (d, 2H, JZ8.2 Hz, ArH). 13C NMR (50 MHz) d
13.9 (Me n-Bu), 14.0 (Me n-Bu), 21.4 (Me p-Tol), 22.5,
22.7, 27.5, 27.8, 28.9 (3Me t-Bu), 30.4, 34.7, 35.9, 69.1
(C-5), 117.9, 125.4 (2C p-Tol), 125.8, 129.6 (2C p-Tol),
140.4, 141.6, 195.7 (C-7). IR (CHCl3): 3380, 2998, 2977,
Data for 16a. RfZ0.39 (30% EtOAc–hexane). [a]2D0ZC
1
29.8 (cZ3.12). H NMR (200 MHz) d 0.71 (d, 3H, JZ
7.3 Hz, Me), 0.73 (t, 3H, JZ7.0 Hz, Me), 0.90 (t, 3H, JZ
6.9 Hz, Me), 1.22–1.50 (m, 6H), 2.20–2.32 (m, 3H), 2.36 (s,
3H, Me p-Tol), 6.35 (t, 1H, JZ7.6 Hz, H-5), 7.22 (d, 2H,
JZ8.8 Hz, ArH), 7.46 (d, 2H, JZ8.2 Hz, ArH). 13C NMR
(50 MHz) d 12.3 (Me), 13.9 (Me), 19.8 (Me), 21.4 (Me
p-Tol), 22.5, 28.5, 29.7, 31.3, 33.0, 125.5 (2C, p-Tol), 129.5
(2C, p-Tol), 135.0, 140.6, 141.1, 148.4. IR (film): 3060,
2980, 2940, 2880, 1600, 1490, 1460, 1400, 1380, 1305,
2890, 1935, 1594, 1496, 1472, 1240, 1087, 1038, 812 cmK1
.
4.3.9. Synthesis of (G)-(5R,SS)-8-n-butyl-6-(p-tolylsulfi-
nyl)-dodeca-6,7-dien-5-ol, 15a and (G)-(5S,SS)-8-n-
butyl-6-(p-tolylsulfinyl)-dodeca-6,7-dien-5-ol, 15b. From
CuI (57 mg, 0.30 mmol) in 3.0 mL of THF, n-BuLi (1.6 M,
0.37 mL, 0.59 mmol) and a mixture of sulfinyl oxiranes 6a
and 6b 34:66 (19 mg, 0.060 mmol) in 0.6 mL of THF
following the above procedure (2 h from K30 8C to rt) was
obtained a mixture of 15a and 15b (37:63). After
chromatography (0–25% EtOAc–CH2Cl2) was isolated
14 mg (64%) of the mixture of allenes as a colorless oil.
1290, 1180, 1150, 1090, 1050, 1020, 920, 910, 810 cmK1
.
MS (CI/CH4): 282, 281 [MC1]C (100%), 263, 247, 139,
123. HRMS calcd for C17H27OS [MC1]C: 281.1575.
Found: 281.1570. Anal Calcd for C17H26OS: C, 72.60; H,
9.21; S, 11.34. Found: C, 72.89; H, 9.15; S, 11.24.
4.3.12. Synthesis of (2R,5S,SS)-(3E)-2-methyl-4-(p-tolyl-
sulfinyl)-1-triphenylsilyloxy-non-3-en-5-ol, 8c. To a cold
(0 8C) solution of 8b (25 mg, 0.08 mmol) in 1 mL of
anhydrous CH2Cl2 was added 3.0 equiv. of Et3N (34 mL,
24 mg, 0.24 mmol), a catalytic amount of DMAP and
1.2 equiv. of Ph3SiCl (28.5 mg, 0.10 mmol). The mixture
was stirred at rt until starting material disappearance (1H,
TLC) and then was quenched with 5% solution of NaHCO3
(4 mL/mmol) and diluted with EtOAc (10 mL/mmol). The
aqueous layer was washed with EtOAc (3!10 mL/mmol)
and the organic extracts were washed with brine, dried over
anhydrous MgSO4 and evaporated under vacuum. Chroma-
tography of the crude (10–50% EtOAc–hexane) afforded
26 mg (57%) of 8c as a colorless oil.
1
Data for 15a (from the mixture). H NMR (200 MHz) d
0.75–0.95 (m, 9H), 1.09–1.70 (m, 12H), 1.83–2.30 (m, 6H),
2.40 (s, 3H, Me p-Tol), 3.79 (br s, 1H, OH), 4.27 (t, 1H, JZ
6.1 Hz, H-5), 7.29 (d, 2H, JZ7.9 Hz, ArH), 7.49 (d, 2H, JZ
8.4 Hz, ArH).
1
Data for 15b (from the mixture). H NMR (200 MHz) d
0.75–0.95 (m, 9H), 1.09–1.70 (m, 12H), 1.83–2.30 (m, 6H),
2.38 (s, 3H, Me p-Tol), 2.75 (br s, 1H, OH), 4.48 (t, 1H, JZ
6.1 Hz, H-5), 7.27 (d, 2H, JZ7.9 Hz, ArH), 7.53 (d, 2H, JZ
8.4 Hz, ArH).
Data for 8c. RfZ0.18 (30% EtOAc–hexane). 1H NMR
(300 MHz) d 0.69 (t, 3H, JZ7.0 Hz, Me n-Bu), 1.00–1.06
(m, 4H), 1.05 (d, 3H, JZ6.7 Hz, Me), 1.20–1.60 (m, 2H,
H-6), 2.31 (s, 3H, Me p-Tol), 2.41 (br s, 1H, OH), 3.01–3.11
(m, 1H, H-2), 3.66 (dd, 1H, JZ9.8, 7.7 Hz, H-1), 3.75 (dd,
1H, JZ9.8, 5.4 Hz, H-1), 4.39 (m, 1H, H-5), 6.20 (d, 1H,
JZ10.6 Hz, H-3), 7.08 (d, 2H, JZ8.1 Hz, ArH), 7.34–7.57
(m, 17H, ArH).
4.3.10. Synthesis of the mesylate of (K)-(5S,SS)-(3Z)-4-
(p-tolylsulfinyl)-non-3-en-5-ol, 7c. To a cold solution
(0 8C) of 7a (55 mg, 0.17 mmol) in 3.5 mL of THF was
added 3 equiv. of Et3N (73.3 mL, 53 mg, 0.52 mmol),
3 equiv. of MsCl (40 mL, 59.5 mg, 0.52 mmol) and the
mixture was stirred for 1 h. After that time, a saturated
solution of NaHCO3 (5 mL) and EtOAc (5 mL) was added
to the reaction mixture. The organic layer was washed with
a saturated solution of NH4Cl, dried over MgSO4 and
evaporated under vacuum. After chromatography on
deactivated silica gel (washed with a 5% solution of
NaHCO3 in MeOH and dried) and using as solvent 20–
50% EtOAc–hexane was obtained 67.0 mg (95%) of 7c as a
yellow oil.
4.3.13. Synthesis of the mesylate of (2R,5S,SS)-(3E)-2-
methyl-4-(p-tolylsulfinyl)-1-triphenylsilyloxy-non-3-en-
5-ol, 8d. From 8c (22 mg, 0.04 mmol), Et3N (22 mL, 16 mg,
0.15 mmol), MsCl (9 mL, 13 mg, 0.12 mmol) and DMAP in
THF following the procedured described for 7c was
obtained after chromatography (5–40% EtOAc–hexane)
16 mg (64%) of 8d as a colorless oil.
Data for 7c. RfZ0.32 (30% EtOAc–hexane). 1H NMR
(200 MHz) d 0.58 (t, 3H, JZ6.5 Hz, Me), 0.70–1.50 (m,
6H), 1.16 (t, 3H, JZ7.4 Hz, Me), 2.37 (s, 3H, Me p-Tol),
2.58 (m, 1H), 2.76 (m, 1H), 3.07 (s, 3H, Me Ms), 5.07 (dd,
1H, JZ9.2, 4.3 Hz, H-5), 6.41 (dd, 1H, JZ8.6, 7.1 Hz,
Data for 8d. RfZ0.20 (30% EtOAc–hexane). 1H NMR
(300 MHz) d 0.59 (t, 3H, JZ7.1 Hz, Me n-Bu), 0.72–0.97
(m, 4H), 1.05 (d, 3H, JZ6.6 Hz, Me), 1.15–1.30 (m, 1H,

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R. Fernandez de la Pradilla et al. / Tetrahedron 60 (2004) 8171–8180
8179
Montero, C.; Tortosa, M. Org. Lett. 2002, 4, 2373–2376. (c)
´ ´
Viso, A.; Fernandez de la Pradilla, R.; Garcıa, A.; Guerrero-
H-6), 1.66–1.80 (m, 1H, H-6), 2.35 (s, 3H, Me p-Tol), 2.95
(s, 3H, Me Ms), 3.08–3.18 (m, 1H, H-2), 3.68 (dd, 1H, JZ
9.8, 8.2 Hz, H-1), 3.80 (dd, 1H, JZ9.8, 4.8 Hz, H-1), 5.06
(dd, 1H, JZ10.4, 3.4 Hz, H-5), 6.50 (d, 1H, JZ11.1 Hz,
H-3), 7.11 (d, 2H, JZ8.1 Hz, ArH), 7.35–7.58 (m, 17H,
ArH).
´
Strachan, C.; Alonso, M.; Tortosa, M.; Flores, A.; Martınez-
´
Ripoll, M.; Fonseca, I.; Andre, I.; Rodrıguez, A. Chem. Eur. J.
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2003, 9, 2867–2876. (d) Fernandez de la Pradilla, R.; Buergo,
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69, 1978–1986. (e) Viso, A.; Fernandez de la Pradilla, R.;
´
´ ´
Lopez-Rodrıguez, M. L.; Garcıa, A.; Flores, A.; Alonso, M.
4.3.14. Synthesis of (2R,3S,SS)-(4E)-2,3-dimethyl-4-(p-
tolylsulfinyl)-1-triphenylsilyloxy-non-4-ene, 17a. From
CuCN (13.6 mg, 0.15 mmol) in 0.5 mL of THF, MeLi
(93 mL, 0.15 mmol) and mesylate 8d (12 mg, 0.02 mmol) in
0.5 mL of THF following the above procedure (40 h at rt)
was obtained a mixture of 17a and 17b (91:9) along with a
45% of starting material. After chromatography (5–40%
EtOAc–hexane) was isolated 8 mg (76%) of 17a as a
colorless oil.
J. Org. Chem. 2004, 69, 1542–1547.
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65, 6462–6473. (b) Marino, J. P.; Anna, L. J.; Fernandez de la
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Pradilla, R.; Martınez, M. V.; Montero, C.; Viso, A.
Data for 17a. RfZ0.27 (30% EtOAc–hexane). [a]2D0ZC
56.1 (cZ0.18). H NMR (400 MHz) d 0.66 (d, 3H, JZ
Tetrahedron Lett. 1996, 37, 8031–8034.
5. For recent reviews on sulfoxide chemistry, see: (a) Fernandez,
I.; Khiar, N. Chem. Rev. 2003, 103, 3651–3705. (b) Hanquet,
1
´
6.9 Hz, Me-2), 0.79 (d, 3H, JZ7.2 Hz, Me-3), 0.90 (t, 3H,
JZ7.2 Hz, Me n-Bu), 1.22–2.24 (m, 8H, H-2, H-3, H-6,
H-7, H-8), 2.36 (s, 3H, Me p-Tol), 3.61 (dd, 1H, JZ10.1,
5.1 Hz, H-1), 3.71 (dd, 1H, JZ10.1, 3.2 Hz, H-1), 6.36 (t,
1H, JZ7.6 Hz, H-5), 7.17 (d, 2H, JZ8.0 Hz, ArH), 7.34–
7.57 (m, 17H, ArH). IR (film): 3065, 2961, 2920, 2855,
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1454, 1428, 1261, 1216, 1116, 807, 758, 700 cmK1
.
MS (ES): 1155 [2MCNa]C, 589 [MCNa]C (100%), 567
[MC1]C.
´ ´
14993. (f) Brebion, F.; Delouvrie, B.; Najera, F.; Fensterbank,
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Acknowledgements
´ ´
6. (a) Fernandez de la Pradilla, R.; Fernandez, J.; Manzano, P.;
´ ´
Mendez, P.; Priego, J.; Tortosa, M.; Viso, A.; Martınez-Ripoll,
This research was supported by CAM (Grant
08.5/0028/2003) and DGI MCYT (Grants BQU2001-0582
and BQU2003-02921). We thank JANSSEN-CILAG
for additional support and MEC for a doctoral fellowship
to M. T.
´
M.; Rodrıguez, A. J. Org. Chem. 2002, 67, 8166–8177.
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(b) Fernandez de la Pradilla, R.; Viso, A. Recent Res. Dev.
Org. Chem. 1998, 2, 343–349.
7. Satoh, T.; Sugimoto, A.; Itoh, M.; Yamakawa, K. Bull. Chem.
Soc. Jpn. 1989, 62, 2942–2947.
8. For a recent review of alkynyl oxiranes, see:Chemla, F.;
Ferreira, F. Curr. Org. Chem. 2002, 6, 539–570.
9. Leading references for the synthesis of chiral allenes: (a)
References and notes
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Fernandez de la Pradilla, R.; Rubio, M. B.; Marino, J. P.; Viso,
A. Tetrahedron Lett. 1992, 33, 4985–4988. (b) Satoh, T.;
Hanaki, N.; Kuramochi, Y.; Inoue, Y.; Hosoya, K.; Sakai, K.
Tetrahedron 2002, 58, 2533–2549. (c) Wei, L. L.; Xian, H.;
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1. (a) Smith, A. B.; Pittram, S. M.; Boldi, A. M.; Gaunt,
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Fujii, N.; Ibuka, T. J. Org. Chem. 1998, 63, 7053–7061. (d)
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10. (a) Fernandez de la Pradilla, R.; Castro, S.; Manzano, P.;
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Martın-Ortega, M.; Priego, J.; Viso, A.; Rodrıguez, A.;
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Fonseca, I. J. Org. Chem. 1998, 63, 4954–4966. (b) Fernandez
de la Pradilla, R.; Castro, S.; Manzano, P.; Priego, J.; Viso, A.
J. Org. Chem. 1996, 61, 3586–3587. (c) Ratios of diastero-
facial isomers vary depending on the epoxidation conditions.
For details see a full account on these processes Ref. 10a.
11. The stereochemical assignment of diastereomers 6a and 6b is
tentative since extensive decomposition upon storage at room
temperature along with the low stereoselectivity found, could
indicate a favourable [2,3]-sigmatropic rearrangement of the
propargylic sulfoxides with loss of the stereochemical integrity
at sulfur.
´
2. (a) Fernandez de la Pradilla, R.; Baile, R.; Tortosa, M. Chem.
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Commun. 2003, 2476–2477. (b) Fernandez de la Pradilla, R.;
12. Sonogashira coupling followed by nucleophilic epoxidation of
related (E)-1-iodo styryl sulfoxide led to an equimolecular

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R. Fernandez de la Pradilla et al. / Tetrahedron 60 (2004) 8171–8180
8180
mixture of unstable alkynyl epoxides therefore we did not
examine the SN20 reactivity of these substrates.
16. Additional data (i.e., X-ray) will be needed for unequivocal
structural assignment of this compound.
17. Spectral data (1H and 13C NMR) of 16a are almost identical to
that encountered for (E)-5(R)-methyl-4(Rs)-(p-tolylsulfinyl)
non-3-ene (compd. 8b in Ref. 3a). As we have previously
observed the newly introduced methyl group appears more
shielded (0.71 ppm) for that relative stereochemistry.
13. Arbitrarily, we termed epoxides b (up) or a (down) regarding
the plane of paper.
14. These results seems to indicate a higly stereocontrolled
pathway of the allylic displacement. The structural
assignment of 14a,b was made on the basis of an anti attack,
however, we cannot accurately establish the stereochemical
outcome since the structural assignment for 6a,b is tentative,
see Ref. 11.
18. The chemical shifts of vinylic protons usually appear down-
field for the E double bond (6.35–6.36). Some similarities can
be observed for the newly introduced methyl group with the
same relative stereochemistry regarding the sulfoxide.
15. Structural assignments of the products are based in the
comparison of NMR data with that of related hydroxy vinyl
sulfoxides from our group previously characterized by X-ray
diffraction analysis. The Z–E stereochemistry is easily
established through the chemical shifts of vinyl protons. For
example 7a (H-3): 6.17 ppm; 11a (H-3): 6.43 ppm. Significant
differences are also found for H-2 protons in these compounds.
19. Paley, R. S.; de Dios, A.; Estroff, L. A.; Lafontaine,
J. A.; Montero, C.; McCulley, D. J.; Rubio, M. B.; Ventura,
´
M. P.; Weers, H. L.; Fernandez de la Pradilla, R.; Castro, S.;
Dorado, R.; Morente, M. J. Org. Chem. 1997, 62, 6326–6343.