Enantiopure alkylidene-1,1-bis-p-tolylsulfoxides as new partners in diastereoselective radical cyclizations

Article abstract of DOI:10.1016/S0957-4166(03)00536-6

Enantiopure alkylidene-1,1-bis-p-tolylsulfoxides have been used as new partners in diastereoselective radical cyclizations. An efficient and highly diastereoselective 6-exo-trig cyclization was observed.

Full text of DOI:10.1016/S0957-4166(03)00536-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2889–2896
Enantiopure alkylidene-1,1-bis-p-tolylsulfoxides as new partners
in diastereoselective radical cyclizations
Franck Brebion, Maxime Vitale, Louis Fensterbank* and Max Malacria*
Laboratoire de Chimie Organique, UMR CNRS 7611, Universite´ Pierre et Marie Curie, Case 229, 4 place Jussieu,
75252 Paris cedex 05, France
Received 30 April 2003; accepted 13 June 2003
Abstract—Enantiopure alkylidene-1,1-bis-p-tolylsulfoxides have been used as new partners in diastereoselective radical cycliza-
tions. An efficient and highly diastereoselective 6-exo-trig cyclization was observed.
© 2003 Elsevier Ltd. All rights reserved.
were obtained for b-alkoxy vinyl sulfoxides,8 while the
1. Introduction
pure carbon systems have so far led to poor results,
even in the case of N-sulfinimines.9 A rationale for this
is the likely absence of control of the s-cis or s-trans
vinyl sulfoxide conformation.10
Radical processes hold nowadays an important position
in the realm of asymmetric synthesis.1,2 This is due in
part to the high compatibility of radical reactions with
a large number of interesting functionalities, notably
present on chiral auxiliaries, and to the possibility of
optimizing the stereoselectivities on using Lewis acids.3
For instance, the addition of a carbon-centered (alkyl
or vinyl) radical to an alkene moiety bearing a chiral
auxiliary has been well-studied (Fig. 1).4 Generally
higher diastereoselectivities are obtained when the addi-
tion occurs a to the chiral auxiliary. Good to excellent
b-diastereoselectivities could also be observed,5 the use
of Lewis acids being critical in the case of chiral
acrylates6 and N-enoyloxazolidinones.7
We have proposed two solutions: The first one was
based on a 5-exo-trig cyclization of a prochiral radical
in an anti-Michael orientation, followed by the well-
established b-elimination of the sulfinyl radical.11
Implying an a priori quite favorable a-selectivity, this
radical addition was highly diastereoselective. More-
over, the presence of bulky Lewis acid MAD could
reverse the stereochemical outcome of the reaction.12
The second solution consists of the implementation of a
second Lewis base on the vinylsulfoxide moiety which
could set the stage for chelation and thus enhance the
diastereoselection by locking the reacting conforma-
tions. This was for instance achieved by Toru who
concentrated on the diastereoselective addition of alkyl
radicals on 2-arylsulfinyl-2-cyclopentenones.13 Our own
approach has focused on enantiopure alkylidene-1,1-
bis-p-tolylsulfoxides as radical acceptors which in addi-
tion to displaying two Lewis basic sites offer the
We have focused for some years on the use of chiral
sulfur-based auxiliaries, mainly sulfoxides, because of
their easy introduction, their low cost and their versatile
final functionalization. Our initial approach, based on
the Michael addition of a vinyl radical onto vinyl
sulfoxides gave mixed results. High diastereoselectivities
Figure 1.
Scheme 1.
* Corresponding authors.
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00536-6

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F. Brebion et al. / Tetrahedron: Asymmetry 14 (2003) 2889–2896
advantage of presenting a C2-symmetry environment
(Scheme 1), and serving as masked chiral ketene equiv-
alents.14 Preliminary results of radical additions are
described herein.
alcohols 6 and 7, but with moderate diastereoselectivity
(Scheme 3). The second one consists of a mild dehydra-
tion of the sulfinyl alcohols with the morpho CDI
reagent.18 Because the two diastereomeric alcohols 6
and 7 do not react at the same rate in the dehydration
reaction which generates separation problems, we pre-
ferred running this step on the separate diastereomers.
Similarly, precursor 9c was obtained in 44% overall
yield from aldehyde 4.
2. Results and discussions
Radical cyclization precursors were synthesized in a
two-step sequence, as previously described,15 from alde-
hydes 2 and 3 that were obtained, respectively, after
simple and double homologation of the known alde-
hyde 116 (Scheme 2). Aldehyde 4 was prepared follow-
ing the same type of chemistry.
We next examined the radical behavior of these new
partners and radical cyclizations were conducted under
the usual conditions using triethylborane as an initia-
tor.19 Initial results with 5-exo precursors 9a were
rather frustrating (Scheme 4). Although complete con-
sumption of the starting material was observed, isola-
tion by chromatography of cyclization product 10a
proved to be difficult because of its instability. This
The first step involves the alkylation of the lithium
anion of (S,S)-bis-p-tolylsulfinylmethane 517 with the
aforementioned aldehydes.15 This proceeded unevent-
fully to provide satisfactory yields of diastereomeric
1
resulted in variable yields of isolated compounds. H
Scheme 2.
Scheme 3.
Scheme 4.

F. Brebion et al. / Tetrahedron: Asymmetry 14 (2003) 2889–2896
2891
NMR of the crude cyclization products suggested a
high diastereoselectivity in the cyclization process, and
among the minor side products that could be observed
we could not ascertain that a minor diastereomer was
formed. The major adduct rapidly decomposed into
dienes 11 as a 1.3:1 mixture of diastereomers,20 pre-
sumably due to spontaneous loss of arylsulfenic acid, a
previously reported phenomenon on some alkylidene
bis-sulfoxides.21 Precursor 9c gave a more stable
cyclization adduct 10c, clearly present as two
diastereomers in a 86:14 ratio. Only traces of diene 13
were observed. A major side product in this reaction
was the Pummerer adduct15 12 whose mechanism of
formation remains to be clarified.
Figure 2.
More fruitful results were obtained with precursor 9b,
since cyclization adducts 10b were stable and could be
fully characterized (Scheme 5). Once again, full con-
sumption of starting material 9b was obtained and
reasonable diastereomeric excesses up to 76% could be
reached. Major diastereomer 10bM gave suitable crys-
tals for an X-ray diffraction analysis which allowed us
to determine the (R) absolute configuration at the
newly formed stereogenic center (Fig. 2).
The X-ray22 view of 10bM shows an additional intrigu-
ing feature of the molecular system: a guest CH2Cl2 is
,
chelated through double hydrogen bonds (2.1–2.4 A)
from the sulfinyl oxygens.23
To rationalize this finding, we propose the following
transition state based on several criteria (Scheme 6).
The crucial one is the conformation of the two sulfinyl
groups of the alkylidene compounds 9b. Based on our
previous findings on vinylsulfoxides,8,12 calculations by
Tietze,10 and minimization of allylic strain,24 we pro-
pose an eclipsed lone pair conformation of the sulfinyl
group cis to the alkyl chain, and a s-cis conformation
for the trans sulfinyl group. Attack of the incoming
radical would then take place anti to the p-tolyl group.
Scheme 6.
We next sought to operate the radical cyclizations in
the chelation mode as in Scheme 1. For this purpose,
we added to the reaction mixture one equivalent of a
bidentate Lewis acid such as ZnBr2 or Et2AlCl. In both
cases,
a complex reaction mixture was obtained
Scheme 5.
(Scheme 7). Three main products were isolated, the
Scheme 7.

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F. Brebion et al. / Tetrahedron: Asymmetry 14 (2003) 2889–2896
expected cyclization adduct 10bM with a similar
diastereoselectivity, accompanied by the reduction
adducts 14 and 15. These compounds presumably orig-
inate from polar reduction by the hydride due to over-
activation of the substrate from the Lewis acids.7 This
complicated reactivity, and the non-alteration of the
diastereoselection in these reactions were not particu-
larly encouraging and no other attempts were made on
these precursors.
g, 25 mmol, 2.5 equiv.). After stirring for 30 min at
0°C, 30 min at rt, the reaction mixture was cooled to
−78°C and a 10 mL THF solution of aldehyde 116 (1.91
g, 10 mmol, 1 equiv.) was added. After 30 min of
stirring at rt, the reaction was complete and usual
aqueous work-up (sat. NH4Cl, NaCl washings, drying
over MgSO4) was operated. Chromatography (PE/EA:
95/5) afforded 3.30 g of an oil (quantitative yield) as a
50:50, E:Z mixture of diastereomers. This mixture was
treated with pyridinium-p-toluenesulfonate (258 mg, 0.5
mmol, 0.05 equiv.) in 100 mL of refluxing acetone
overnight, then hydrolized with water. After extraction
with ether and drying with MgSO4, chromatography
(PE/Et2O: 95/5) afforded 1.54 g (75%) of 2 as an oil. IR
(neat): 2980, 1720, 1620 cm−1. 1H NMR (200 MHz,
CDCl3) l 1.18 (s, 6H, CH3-C-CH3), 2.46 (d, J=2.6 Hz,
2H, CH2CHO), 2.59 (s, 2H, CH2-CBr), 5.58 (d, J=1.2
Hz, 1H, =CHH), 5.61 (d, J=1.2 Hz, 1H, =CHH),
9.88 (t, J=2.6 Hz, 1H, CHO). 13C NMR (50 MHz,
CDCl3) l 27.8 (CH3-C-CH3), 34.3 (CH3-C-CH3), 52.7
(CH2), 54.1 (CH2), 121.5 (=CH2), 129.1 (CBr), 202.8
(CHO). Anal. calcd for C8H13BrO: C, 46.85; H, 6.39.
Found: C, 46.70; H, 6.59.
In conclusion, alkylidene-1,1-bis-p-tolylsulfoxides have
been used for the first time in radical cyclizations.
Although, some of the cyclization reactions were
plagued by the instability of the cyclization products or
side processes, the efficiency of these new partners as
radical acceptor was demonstrated. Moreover, high
diastereoselectivities could be observed in the 6-exo-trig
case. The application of Lewis acids on other substrates
in order to reach a highly organized chelated transition
state is now in progress and will be reported in due
course.
3. Experimental
3.1. General
3.1.2. 4,4-Dimethyl-6-bromo-hept-6-en-1-al 3. Following
the same procedure from 2 (1.82 g, 8.9 mmol), chro-
matography (PE/Et2O: 95/5) afforded 1.72 g (89%) of 3
1
All reactions were run under an argon or nitrogen
atmosphere in anhydrous solvents and dried flasks.
Thin layer chromatography (TLC) was performed on
Merck silica gel 60 F 254 and revealed with either an
ultraviolet lamp (u=254 nm) or a p-anisaldehyde solu-
tion. Flash column chromatography has been per-
formed with silica gel Merck Geduran SI (40–63 nm).
Solvents were systematically distilled prior to be used.
EA refers to ethyl acetate, PE to petroleum ethers. The
aldehydes were dried over CaSO4 and distilled. IR
spectra were recorded on a Perkin–Elmer 1420 spec-
as an oil. IR (neat): 2960, 1730, 1620 cm−1. H NMR
(200 MHz, CDCl3) l 1.00 (s, 6H, CH3-C-CH3), 1.68 (t,
J=6.5 Hz, 2H, CH2CH2CHO), 2.44 (s, 2H, CH2-CBr),
2.47 (m, 2H, CH2CHO), 5.55 (d, J=1.3 Hz, 1H,
=CHH), 5.58 (d, J=1.3 Hz, 1H, =CHH), 9.81 (t,
J=1.6 Hz, 1H, CHO). 13C NMR (50 MHz, CDCl3) l
27.1 (CH3-C-CH3), 33.4 (CH2), 33.8 (CH3-C-CH3),
39.4 (CH2), 52.4 (CH2), 120.9 (=CH2), 129.7 (CBr),
202.7 (CHO). Anal. calcd for C9H15BrO: C, 49.33; H,
6.90. Found: C, 49.28; H, 7.09.
trometer and on a Bruker Tensor 27. H and 13C NMR
3.1.3. 3,3-Dimethyl-5-bromo-6-methyl-hept-5-en-1-al 4.
IR (neat): 2960, 2930, 1860, 1720, 1600, 1380, 1150
cm−1. 1H NMR (200 MHz, CDCl3) l 1.15 (s, 6H,
CH3-C-CH3), 1.77 (s, 3H, =C(CH3)2), 1.90 (s, 3H,
=C(CH3)2), 2.42 (d, J=2.7 Hz, 2H, CH2CHO), 2.68 (s,
2H, CH2-CBr), 9.87 (t, J=2.7 Hz, 1H, CHO). 13C
NMR (50 MHz, CDCl3) l 26.9 (CH3-C-CH3), 28.2
(=C(CH3)2), 35.4 (CH3-C-CH3), 48.8 (CH2), 54.9
(CH2), 114.1 (CBr), 128.2 (=C(CH3)2), 203.2 (CHO).
1
spectra were recorded at room temperature, either at
200 MHz and 50 MHz on a AC200 Bruker spectrome-
ter, or at 250 MHz and 63 MHz on a AC250 Bruker, or
at 400 MHz and 100 MHz respectively on an ARX400
Bruker spectrometer. Shifts are given in ppm and refer-
enced from the solvent residual signal (7.26 ppm for
CDCl3) for proton NMR. For carbon NMR, shifts are
referenced from the solvent central peak (77.3 ppm for
CDCl3). Coupling constants (J) are given in hertz (Hz).
The letters m, s, d, t, q, hept mean, respectively, multi-
plet, singulet, doublet, triplet, quadruplet, heptuplet.
Optical rotations were measured on a Perkin Elmer 343
polarimeter. Elemental analysis were performed by the
Service Re´gional de Microanalyse de l’Universite´ Pierre
et Marie Curie. Melting points were obtained on a
Reichert apparatus and are uncorrected.
3.2. General procedure for the synthesis of bis-sulfinyl
alcohols 6 and 7
To a solution of (S,S)-bis-p-tolylsulfinylmethane 5 (1
equiv.) in THF (0.025 M) were added, at −40°C, n-
BuLi in hexanes (1.2 equiv.) and the solution was
stirred at −40°C for 1 h. Then, the reaction mixture was
cooled to −78°C and the freshly distilled aldehyde was
added neat (1.5 equiv.). The reaction was stirred at this
temperature for 0.5 h and at −40°C for 1 h (only 1 h at
−78°C in the case of 6a and 6b). Then, it was quenched
at this temperature with an aqueous saturated NH4Cl
solution. The THF was evaporated and then extracted
twice with CH2Cl2 and the combined organic layers
were washed with brine and dried over MgSO4. The
3.1.1. 3,3-Dimethyl-5-bromo-hex-5-en-1-al 2. To a THF
solution (25 mL) of di-isopropylamine (3.5 mL, 25
mmol, 2.5 equiv.) at 0°C, was added 16.7 mL of
n-butyllithium (1.5 M in hexanes, 25 mmol, 2.5 equiv.).
After 5 min of stirring at 0°C, this mixture was cannu-
lated
into
a
25
mL
THF
solution
of
(methoxymethyl)triphenylphosphonium chloride (8.84

F. Brebion et al. / Tetrahedron: Asymmetry 14 (2003) 2889–2896
2893
residue was purified by flash chromatography to give by
order of elution the two diastereomeric alcohols 7 then
6.
arom), 7.40 (d, J=8.4 Hz, 2H, arom), 7.66 (d, J=8.4
Hz, 2H, arom). 13C NMR (63 MHz, CDCl3) l 21.3
(p-Tol), 21.5 (p-Tol), 26.9, 27.1 (CH3-C-CH3), 29.7
(CH2), 33.7 (CH3-C-CH3), 36.9 (CH2), 52.1 (CH2), 67.6
(CH-OH), 92.2 (CH(SOp-Tol)2), 120.5 (=CH2), 123.7
(2 CH arom), 124.7 (2 CH arom), 130.2 (4 CH arom),
129.7, 136.6, 139.5, 141.7, 142.3 (4 C arom+=CBr).
Anal. calcd for C24H31BrO3S2: C, 56.35; H, 6.11.
Found: C, 56.24; H, 6.22.
3.2.1. (SS,SS,2S)-1,1-Di-p-tolylsulfinyl-4,4-dimethyl-6-
bromo-hept-6-en-2-ol 6a. Using the general procedure
from 5 (195 mg, 0.66 mmol) and aldehyde 2 (205 mg, 1
mmol), chromatography (pentane/EA, from 75/25 to
50/50) afforded 189 mg (57%) of 6a as a slightly yellow
gum; [h]2D0 +60.0 (c 1.05, CHCl3). IR (neat): 3405, 3011,
1
2960, 2926, 1622, 1492, 1083, 1050, 811, 755 cm−1. H
3.2.4. (SS,SS,2R)-1,1-Di-p-tolylsulfinyl-5,5-dimethyl-7-
bromo-oct-7-en-2-ol 7b. The second minor fraction con-
NMR (400 MHz, CDCl3) l 0.91 (s, 3H, CH3-C-CH3),
0.92 (s, 3H, CH3-C-CH3), 1.20 (d, J=14.4 Hz, 1H,
CHH-CHOH), 1.94 (dd, J=14.4, 8.8 Hz, 1H, CHH-
CHOH), 2.35 (s, 3H, p-Tol), 2.36–2.39 (mAB, 2H, =
CBr-CH2), 2.47 (s, 3H, p-Tol), 3.32 (s, 1H,
CH(SOp-Tol)2), 4.76 (d, J=8.8 Hz, 1H, CH-OH), 5.39
(s, 1H, =CHH), 5.42 (s, 1H, =CHH), 7.01 (d, J=8.3
Hz, 2H, arom), 7.22 (d, J=7.8 Hz, 2H, arom), 7.40 (d,
J=7.8 Hz, 2H, arom), 7.63 (d, J=8.3 Hz, 2H, arom).
13C NMR (50 MHz, CDCl3) l 21.5 (p-Tol), 21.7 (p-
Tol), 27.9, 28.1 (CH3-C-CH3), 34.7 (CH3-C-CH3), 46.3
(CH2), 52.3 (CH2), 64.8 (CH-OH), 93.2 (CH(SOp-
Tol)2), 121.1 (=CH2), 123.8 (2 CH arom), 124.7 (2 CH
arom), 129.7 (=CBr), 130.5 (4 CH arom), 138.2, 139.8,
142.0, 142.4 (4 C arom). Anal. calcd for C23H29BrO3S2:
C, 55.53; H, 5.88. Found: C, 55.42; H, 5.88.
1
sisted of 474 mg (29%) of 7b as an oil. H NMR (250
MHz, CDCl3) l 0.95 (s, 3H, CH3-C-CH3), 0.96 (s, 3H,
CH3-C-CH3), 1.33 (m, 1H, CH2), 1.61 (m, 1H, CH2),
1.75 (m, 1H, CH2), 1.99 (m, 1H, CH2), 2.32 (s, 3H,
p-Tol), 2.39 (s, 2H, =CBr-CH2), 2.47 (s, 3H, p-Tol),
3.64 (d, J=8.3 Hz, 1H, CH(SOp-Tol)2), 4.50 (m, 1H,
CH-OH), 5.52 (bs, 1H, =CHH), 5.54 (d, J=1.5 Hz,
1H, =CHH), 6.77 (d, J=8.2 Hz, 2H, arom), 7.10 (d,
J=8.2 Hz, 2H, arom), 7.37 (d, J=8.2 Hz, 2H, arom),
7.52 (d, J=8.2 Hz, 2H, arom). 13C NMR (63 MHz,
CDCl3) l 21.6 (p-Tol), 21.8 (p-Tol), 27.3 (CH3-C-
CH3), 29.4 (CH2), 34.2 (CH3-C-CH3), 37.5 (CH2), 51.8
(CH2), 70.8 (CH-OH), 90.0 (CH(SOp-Tol)2), 120.8 (=
CH2), 124.4 (2 CH arom), 125.2 (2 CH arom), 130.3 (2
CH arom+=CBr), 130.5 (2 CH arom), 136.9, 141.2,
141.9, 142.9 (4 C arom).
3.2.2. (SS,SS,2R)-1,1-Di-p-tolylsulfinyl-4,4-dimethyl-6-
bromo-hept-6-en-2-ol 7a. The second minor fraction
consisted of 57 mg (17%) of 7a as a colorless oil; [h]D20
+35.0 (c 0.8, CHCl3). IR (neat): 3380, 3039, 2961, 2927,
3.3. General procedure for the dehydration of bis-sulfi-
nyl alcohols 6 and 7
1
1713, 1623, 1493, 1084, 1040, 892, 811, 733 cm−1. H
To a solution of alcohol 6 or 7 (1 equiv.) in CH3CN
(0.1 M) were added (1.5–2.0 equiv.) of 1-cyclohexyl-3-
(2-morpholinoethyl)-carbodiimide metho-p-toluenesul-
fonate (8) and a catalytic amount of CuCl2 (0.1 equiv.).
The reaction was monitored by TLC and was generally
over after 2–3 h between 40 and 70°C. After cooling,
the reaction mixture was diluted in CH2Cl2 and filtered
over a short pad of Celite and silica and concentrated
in vacuo.
NMR (400 MHz, CDCl3) l 1.08 (s, 3H, CH3-C-CH3),
1.09 (s, 3H, CH3-C-CH3), 1.77 (dd, J=14.4, 9.4 Hz,
1H, CHH-CHOH), 1.94 (d, J=14.4 Hz, 1H, CHH-
CHOH), 2.29 (s, 3H, p-Tol), 2.45 (s, 3H, p-Tol), 2.52
(s, 2H, =CBr-CH2), 3.57 (d, J=8.8 Hz, 1H, CH(SOp-
Tol)2), 4.76 (m, 1H, CH-OH), 5.51 (s, 1H, =CHH),
5.53 (s, 1H, =CHH), 6.71 (d, J=8.1 Hz, 2H, arom),
7.08 (d, J=8.1 Hz, 2H, arom), 7.36 (d, J=8.1 Hz, 2H,
arom), 7.50 (d, J=8.1 Hz, 2H, arom). 13C NMR (50
MHz, CDCl3) l 21.5 (p-Tol), 21.7 (p-Tol), 27.6, 27.9
(CH3-C-CH3), 34.8 (CH3-C-CH3), 46.2 (CH2), 53.3
(CH2), 68.3 (CH-OH), 90.8 (CH(SOp-Tol)2), 121.2
(=CH2), 124.3 (2 CH arom), 125.1 (2 CH arom), 130.1
(=CBr), 130.2 (2 CH arom), 130.5 (2 CH arom), 136.9,
141.0, 141.8, 142.8 (4 C arom).
3.3.1.
(SS,SS)-1,1-Di-p-tolylsulfinyl-4,4-dimethyl-6-
bromo-1,6-heptadiene 9a. Using the general procedure
from 6a (135 mg, 0.27 mmol), filtration afforded 130
mg (quantitative yield) of 9a as a white solid: mp
75–77°C; [h]2D0 −2.6 (c 1.05, CHCl3). IR (neat): 3060,
1
2970, 2930, 1620, 1590, 1480, 1080, 1050, 895 cm−1. H
NMR (400 MHz, CDCl3) l 1.13 (s, 3H, CH3-C-CH3),
1.14 (s, 3H, CH3-C-CH3), 2.30 (s, 3H, p-Tol), 2.31 (s,
3H, p-Tol), 2.50–2.59 (mAB, 2H, =CBr-CH2), 2.60 (dd,
J=15.2, 6.1 Hz, 1H, CHH-CH=C(SOp-Tol)2), 2.84
(dd, J=15.2, 9.6 Hz, 1H, CHH-CH=C(SOp-Tol)2),
5.59 (d, J=1.5 Hz, 1H, =CHH), 5.61 (d, J=1.5 Hz,
1H, =CHH), 6.96 (d, J=8.1 Hz, 2H, arom), 6.99 (s,
4H, arom), 7.20 (d, J=8.1 Hz, 2H, arom), 7.23 (dd,
J=9.6, 6.1 Hz, 1H, CH=C(SOp-Tol)2). 13C NMR (100
MHz, CDCl3) l 21.3 (p-Tol), 21.5 (p-Tol), 27.2 (CH3-
C-CH3), 35.6 (CH3-C-CH3), 40.9 (CH2), 52.5 (CH2),
121.5 (=CH2), 124.2 (2 CH arom), 126.3 (2 CH arom),
129.0 (=CBr), 129.5 (2 CH arom), 129.6 (2 CH arom),
139.9 (CH=C(SOp-Tol)2), 137.6, 139.6, 141.1, 142.4 (4
C arom), 150.2 (CH=C(SOp-Tol)2).
3.2.3. (SS,SS,2S)-1,1-Di-p-tolylsulfinyl-5,5-dimethyl-7-
bromo-oct-7-en-2-ol 6b. Using general procedure from 5
(940 mg, 3.2 mmol) and aldehyde 3 (1.05 g, 4.8 mmol),
chromatography (pentane/EA, from 80/20 to 50/50)
afforded 719 mg (44%) of 6b as a white gum; [h]D20
+107.5 (c 1.0, CHCl3). IR (neat): 3400, 3000, 2980,
1
1625, 1600, 1490, 1100, 1070, 910, 830 cm−1. H NMR
(250 MHz, CDCl3) l 0.83 (s, 3H, CH3-C-CH3), 0.84 (s,
3H, CH3-C-CH3), 1.01 (m, 1H, CH2), 1.24 (m, 1H,
CH2), 1.69 (m, 1H, CH2), 2.25 (s, 2H, =CBr-CH2),
2.34 (m, 1H, CH2), 2.34 (s, 3H, p-Tol), 2.46 (s, 3H,
p-Tol), 3.34 (s, 1H, CH(SOp-Tol)2), 4.40 (m, 1H, CH-
OH), 5.40 (s, 1H, =CHH), 5.45 (s, 1H, =CHH), 7.03
(d, J=8.4 Hz, 2H, arom), 7.22 (d, J=8.4 Hz, 2H,

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F. Brebion et al. / Tetrahedron: Asymmetry 14 (2003) 2889–2896
3.3.2.
(SS,SS)-1,1-Di-p-tolylsulfinyl-5,5-dimethyl-7-
3.4.1. (SS,SS)-1-(Di-p-tolylsulfinylmethyl)-2-methylene-
4,4-dimethyl-cyclopentane 10a. Chromatography (pen-
tane/EA, from 100/0 to 70/30) afforded 10a as a white
solid which decomposes into dienes 11: mp 92–93°C;
bromo-1,7-octadiene 9b. Using the general procedure
from 6b (717 mg, 1.4 mmol), filtration afforded 690 mg
(quantitative yield) of 9b as a white solid: mp 103–
105°C; [h]2D0 −3.7 (c 1.06, CHCl3). IR (neat): 3040, 2965,
2922, 1622, 1594, 1492, 1450, 1393, 1082, 1044, 1015,
1
[h]2D0 36.1 (c 1.35, CHCl3). H NMR (250 MHz, CDCl3)
l 0.83 (s, 3H, CH3-C-CH3), 0.86 (s, 3H, CH3-C-CH3),
2.02 (s, 2H, =C-CH2), 2.36 (s, 3H, p-Tol), 2.42 (s, 3H,
p-Tol), 2.60 (dd, J=15.0, 6.2 Hz, 1H, CHH-CH-
CH(SOp-Tol)2), 2.84 (dd, J=15.0, 9.6 Hz, 1H, CHH-
CH-CH(SOp-Tol)2), 3.56 (m, 1H, CH-CH(SOp-Tol)2),
3.72 (d, J=4.9 Hz, 1H, CH(SOp-Tol)2), 5.21 (d, J=2.0
Hz, 1H, =CHH), 5.57 (d, J=2.0 Hz, 1H, =CHH),
7.19 (m, 4H, arom), 7.29 (d, J=7.9 Hz, 2H, arom), 7.47
(d, J=7.9 Hz, 2H, arom).
803, 622 cm−1. H NMR (400 MHz, CDCl3) l 1.02 (s,
1
6H, CH3-C-CH3), 1.58 (m, 2H, CH2), 2.30 (s, 3H,
p-Tol), 2.32 (s, 3H, p-Tol), 2.55 (s, 2H, =CBr-CH2),
2.56 (m, 1H, CHH-CH=C(SOp-Tol)2), 2.79 (m, 1H,
CHH-CH=C(SOp-Tol)2), 5.54 (s, 1H, =CHH), 5.57
(s, 1H, =CHH), 6.96–7.00 (m, 6H, arom), 7.08 (dd,
J=8.8, 6.9 Hz, 1H, CH=C(SOp-Tol)2), 7.21 (d, J=8.1
Hz, 2H, arom). 13C NMR (63 MHz, CDCl3) l 21.4
(p-Tol), 21.6 (p-Tol), 24.9 (CH2), 27.2, 27.3 (CH3-C-
CH3), 34.4 (CH3-C-CH3), 40.5 (CH2), 52.3 (CH2), 121.0
(=CH2), 124.2 (2 CH arom), 126.3 (2 CH arom), 129.6
(2 CH arom+=CBr), 129.7 (2 CH arom), 143.7 (CH=
C(SOp-Tol)2), 137.8, 139.5, 141.1, 142.5 (4 C arom),
3.4.2. (SS,SS,1R)-1-(Di-p-tolylsulfinylmethyl)-2-methyl-
ene-4,4-dimethyl-cyclohexane 10bM. Chromatography
(pentane/EA, from 95/5 to 70/30) afforded 10bM as a
white solid: mp 104–106°C; [h]2D0 −58.5 (c 1.0, CHCl3).
IR (neat): 3036, 2970, 1640, 1453, 1210, 1070, 1040, 810
cm−1. 1H NMR (400 MHz, CDCl3) l 0.68 (m, 1H,
CHH-CH2-CH-CH(SOp-Tol)2), 0.83 (s, 3H, CH3-C-
CH3), 0.86 (s, 3H, CH3-C-CH3), 0.95 (m, 1H, CHH-
CH2-CH-CH(SOp-Tol)2), 1.56 (m, 1H, CHH-CH-
CH(SOp-Tol)2), 1.74 (m, 1H, CHH-CH-CH(SOp-
Tol)2), 1.87 (d, J=13.3 Hz, 1H, =C-CHH), 2.01 (d,
J=13.3 Hz, 1H, =C-CHH), 2.31 (s, 3H, p-Tol), 2.46
(s, 3H, p-Tol), 3.52 (m, 1H, CH-CH(SOp-Tol)2), 3.67
(d, J=10.9 Hz, 1H, CH(SOp-Tol)2), 5.03 (s, 1H, =
CHH), 5.32 (s, 1H, =CHH), 6.65 (d, J=8.1 Hz, 2H,
arom), 7.08 (d, J=8.1 Hz, 2H, arom), 7.41 (d, J=8.1
Hz, 2H, arom), 7.53 (d, J=8.1 Hz, 2H, arom). 13C
NMR (100 MHz, CDCl3) l 21.3 (p-Tol), 21.6 (p-Tol),
25.4 (CH3-C-CH3), 25.6 (CH2-CH-CH(SOp-Tol)2),
31.6 (CH3-C-CH3), 32.6 (CH3-C-CH3), 33.8 (CH2-CH2-
CH-CH(SOp-Tol)2), 38.2 (CH-CH(SOp-Tol)2), 46.9 (=
C-CH2), 85.2 (CH(SOp-Tol)2), 115.2 (=CH2), 123.3 (2
CH arom), 125.0 (2 CH arom), 130.0 (2 CH arom),
130.3 (2 CH arom), 138.9, 140.7, 141.6, 142.1, 143.4 (4
C arom+C=CH2).
144.9
(CH=C(SOp-Tol)2).
Anal.
calcd
for
C24H29BrO2S2: C, 58.41; H, 5.91. Found: C, 58.30; H,
5.95.
3.3.3.
(SS,SS)-1,1-Di-p-tolylsulfinyl-4,4-dimethyl-6-
bromo-7-methyl-1,6-octadiene 9c. Orange oil; [h]2D0 −15.0
(c 0.7, CHCl3). IR (neat): 3052, 2959, 2918, 1595, 1491,
1468, 1449, 1082, 1045, 1014, 803, 733 cm−1. H NMR
1
(400 MHz, CDCl3) l 1.03 (s, 3H, CH3-C-CH3), 1.05 (s,
3H, CH3-C-CH3), 1.71 (s, 3H, =C(CH3)2), 1.85 (s, 3H,
=C(CH3)2), 2.22 (s, 3H, p-Tol), 2.23 (s, 3H, p-Tol),
2.57 (dd, J=14.9, 6.3 Hz, 1H, CHH-CH=C(SOp-
Tol)2), 2.60 (s, 2H, =CBr-CH2), 2.79 (dd, J=14.9, 9.4
Hz, 1H, CHH-CH=C(SOp-Tol)2), 6.87–6.94 (m, 6H,
arom), 7.11 (d, J=8.1 Hz, 2H, arom), 7.20 (dd, J=9.4,
6.3 Hz, 1H, CH=C(SOp-Tol)2). 13C NMR (100 MHz,
CDCl3) l 21.3, 21.4, 21.9, 26.0, 27.3, 27.5 (6 CH3), 37.3
(CH3-C-CH3), 41.5 (CH2), 48.7 (CH2), 117.1
(=C(CH3)2), 124.1 (2 CH arom), 126.2 (2 CH arom),
129.4 (2 CH arom), 129.5 (2 CH arom), 140.5 (CH=
C(SOp-Tol)2), 134.4, 137.6, 139.7, 141.0, 142.3 (4 C
arom+=CBr), 149.8 (CH=C(SOp-Tol)2).
3.4.3. Characteristic signals for (SS,SS,1S)-1-(di-p-tolyl-
sulfinylmethyl)-2-methylene-4,4-dimethyl-cyclohexane
10bm. 1H NMR (400 MHz, CDCl3) l 2.29 (s, 3H,
p-Tol), 2.46 (s, 3H, p-Tol), 3.07 (m, 1H, CH-CH(SOp-
Tol)2), 3.77 (d, J=5.6 Hz, 1H, CH(SOp-Tol)2), 4.48 (s,
1H, =CHH), 4.64 (s, 1H, =CHH), 6.75 (d, J=8.2 Hz,
2H, arom), 7.05 (d, J=8.2 Hz, 2H, arom), 7.38 (d,
J=8.2 Hz, 2H, arom), 7.59 (d, J=8.2 Hz, 2H, arom).
3.4. General procedure for the radical cyclization of
compounds 9
Et3B/O2 induced radical cyclizations: To a solution of
alkylidene bis-sulfoxide (1 equiv.) in toluene (0.02 M)
were added, at 0°C, 10 equiv. of Et3B (1 M in hexane),
n-Bu3SnH (2 equiv.) and the radical process was ini-
tiated by addition of air (10 mL). The solution was
stirred at 0°C and air (10 mL) was added every hour
until completion (4–9 h). The reaction mixture was
concentrated in vacuo and the residue purified by flash
chromatography.
3.4.4. (SS,SS)-1-(Di-p-tolylsulfinylmethyl)-2-isopropyli-
dene-4,4-dimethyl-cyclopentane 10c. Chromatography
(pentane/EA, from 95/5 to 70/30) afforded 10c (mixture
of two diastereoisomers in a 86: 14 ratio) as a white
solid: IR of both dias. (neat): 2955, 2921, 2861, 1595,
1
Photochemically induced radical cyclizations: To a
solution of alkylidene bis-sulfoxide (1 equiv.) in
degassed toluene (0.02 M) were added AIBN (0.3
equiv.) and n-Bu3SnH (1.5 equiv.). The solution was
cooled to 0°C and irradiated with a sunlamp (Osram
Ultra-Vitalux®) until completion (4 hours). The reac-
tion mixture was concentrated in vacuo and the residue
purified by flash chromatography.
1492, 1464, 1118, 1081, 1049, 808 cm−1. H NMR of
major dias. (400 MHz, CDCl3) l 0.70 (s, 3H, CH3-C-
CH3), 0.86 (s, 3H, CH3-C-CH3), 1.47 (m, 2H, CH2-CH-
CH(SOp-Tol)2), 1.57 (s, 3H, =C(CH3)2), 1.66 (s, 3H,
=C(CH3)2), 1.87 (d, J=13.9 Hz, 1H, =C-CHH), 2.00
(d, J=13.9 Hz, 1H, =C-CHH), 2.37 (s, 3H, p-Tol),
2.44 (s, 3H, p-Tol), 3.46 (m, 1H, CH-CH(SOp-Tol)2),
3.84 (d, J=6.3 Hz, 1H, CH(SOp-Tol)2), 7.16 (d, J=8.4

F. Brebion et al. / Tetrahedron: Asymmetry 14 (2003) 2889–2896
2895
Hz, 2H, arom), 7.23 (d, J=8.4 Hz, 2H, arom), 7.38 (d,
J=8.1 Hz, 2H, arom), 7.59 (d, J=8.1 Hz, 2H, arom).
13C NMR of major dias. (100 MHz, CDCl3) l 21.4,
21.6 (2C), 21.8 (2 p-Tol+=C(CH3)2), 28.4, 29.4 (CH3-
C-CH3), 37.3 (CH-CH(SOp-Tol)2), 37.9 (CH3-C-CH3),
46.0, 46.1 (CH2), 93.7 (CH(SOp-Tol)2), 124.1 (2 CH
arom), 125.7 (2 CH arom), 129.9 (2 CH arom), 130.3 (2
CH arom), 127.2, 134.3, 139.7, 141.0 (2C), 142.7 (4 C
arom+2 vinyl).
3.4.8. (RS)-1-(2-Isopropylidene-4,4-dimethyl-cyclopentyl-
idenemethanemethyl)-p-tolylsulfoxide 13. Colorless oil;
[h]2D0 −274.0 (c 1.3, CHCl3). IR (neat): 3036, 2953, 2921,
2864, 1647, 1597, 1492, 1463, 1366, 1081, 1037, 1013,
1
804, 758 cm−1. H NMR (400 MHz, CDCl3) l 0.94 (s,
3H, CH3-C-CH3), 1.07 (s, 3H, CH3-C-CH3), 1.77 (s,
3H, =C(CH3)2), 2.06 (s, 3H, =C(CH3)2), 2.17–2.32 (2
mAB, 4H, =C-CH2), 2.39 (s, 3H, p-Tol), 5.93 (s, 1H,
=CH(SOp-Tol)), 7.26 (d, J=8.1 Hz, 2H, arom), 7.53
(d, J=8.1 Hz, 2H, arom). 13C NMR (100 MHz,
CDCl3) l 21.6 (p-Tol), 22.8, 25.2 (=C(CH3)2), 29.5,
29.7 (CH3-C-CH3), 35.6 (CH3-C-CH3), 46.1 (CH2),
50.8 (CH2), 124.7 (2 CH arom), 127.4 (=CH(SOp-
Tol)), 130.1 (2 CH arom), 134.2, 133.8, 141.1, 142.6,
153.9 (2 C arom+3 vinyl).
3.4.5. Characteristic signals for minor diastereomer of
10c. 1H NMR (400 MHz, CDCl3) l 3.64 (m, 1H,
CH-CH(SOp-Tol)2), 4.05 (d, J=3.0 Hz, 1H, CH(SOp-
Tol)2).
3.4.6. (RS)-1-(2-Methylene-4,4-dimethyl-cyclopentylidene-
methanesulfinyl)-4-methyl-benzene 11. Chromatography
(pentane/EA, from 100/0 to 70/30) afforded 11 (two
3.4.9.
(SS,SS)-1,1-Di-p-tolylsulfinyl-5,5-dimethyl-7-
bromo-oct-7-ene 14. Chromatography (pentane/EA,
from 95/5 to 75/25) afforded 14 as a white solid: mp
107–109°C; [h]2D0 +106.0 (c 1.0, CHCl3). IR (neat): 3040,
1
diastereomers majo:mino, 1.3:1) as an orange oil; H
1
NMR (400 MHz, CDCl3) l 1.00 (s, 3H, CH3-C-CH3 of
majo), 1.04 (s, 3H, CH3-C-CH3 of majo), 1.05 (s, 3H,
CH3-C-CH3 of mino), 1.08 (s, 3H, CH3-C-CH3 of
mino), 2.27–2.40 (m, 6H, CH2=C-CH2 of majo+CH2-
C=CH(SOp-Tol) of majo and mino), 2.40 (s, 3H,
p-Tol of majo), 2.40 (s, 3H, p-Tol of mino), 2.53 (dd,
J=16.4, 2.2 Hz, 1H, CH2=C-CHH of mino), 2.80 (dd,
J=16.4, 2.0 Hz, 1H, CH2=C-CHH of mino), 5.09 (s,
1H, =CHH of mino), 5.42 (s, 1H, =CHH of majo),
5.46 (t, J=2.2 Hz, 1H, =CHH of mino), 5.92 (s, 1H,
=CHH of majo), 6.16 (s, 1H, =CH(SOp-Tol) of
majo), 6.46 (t, J=2.0 Hz, 1H, =CH(SOp-Tol) of
mino), 7.30 (d, J=8.1 Hz, 2H, arom of majo), 7.31 (d,
J=8.4 Hz, 2H, arom of mino), 7.50 (d, J=8.4 Hz, 2H,
arom of mino), 7.53 (d, J=8.1 Hz, 2H, arom of majo).
13C NMR (100 MHz, CDCl3) l 21.4 (2 p-Tol), 27.7,
27.8, 27.9 (2C) (CH3-C-CH3), 37.0, 37.5 (CH3-C-CH3),
46.7 (CH2-C=CH(SOp-Tol) of mino), 48.0, 49.8, 50.8
(CH2), 110.4 (=CH2 of mino), 117.2 (=CH2 of majo),
2922, 1620, 1493, 1083, 1053, 905, 810 cm−1. H NMR
(400 MHz, CDCl3) l 0.68 (s, 3H, CH3-C-CH3), 0.69 (s,
3H, CH3-C-CH3), 0.80–0.95 (m, 4H, CH2-CH2-
C(CH3)2), 1.53 (m, 1H, CHH-CH(SOp-Tol)2), 1.95 (m,
1H, CHH-CH(SOp-Tol)2), 2.11 (s, 2H, =CH-CH2),
2.36 (s, 3H, p-Tol), 2.43 (s, 3H, p-Tol), 3.39 (t, J=5.0
Hz, 1H, CH(SOp-Tol)2), 5.33 (s, 1H, =CHH), 5.44 (s,
1H, =CHH), 7.25 (s, 4H, arom), 7.36 (d, J=8.1 Hz,
2H, arom), 7.63 (d, J=8.1 Hz, 2H, arom). 13C NMR
(100 MHz, CDCl3) l 19.4 (CH2), 20.6 (p-Tol), 20.8
(p-Tol), 21.5 (CH2), 27.3 (CH3-C-CH3), 34.0 (CH3-C-
CH3), 41.1 (CH2), 52.0 (CH2), 89.2 (CH(SOp-Tol)2),
120.5 (=CH2), 124.1 (2 CH arom), 125.7 (2 CH arom),
130.2 (=CBr), 130.3 (2 CH arom), 130.4 (2 CH arom),
138.1, 139.4, 141.8, 143.1 (4 C arom).
3.4.10. (SS,SS)-1,1-Di-p-tolylsulfinyl-5,5-dimethyl-oct-7-
ene 15. Chromatography (pentane/EA, from 95/5 to
75/25) afforded 15 as a colorless oil: [h]2D0 +115.0 (c 1.0,
CHCl3). IR (neat): 3053, 2956, 2924, 1595, 1492, 1469,
124.3 (2 2 CH arom), 124.4 (2 2 CH arom), 126.3
ꢀ
ꢀ
1083, 1056, 911, 810, 731 cm−1. H NMR (400 MHz,
(=CH(SOp-Tol) of mino), 130.3 (=CH(SOp-Tol) of
majo), 130.3 (2 2 CH arom), 141.3 (2C), 141.9, 142.1,
1
ꢀ
CDCl3) l 0.58 (s, 6H, CH3-C-CH3), 0.65–0.80 (m, 4H,
CH2-CH2-C(CH3)2), 1.51 (m, 1H, CHH-CH(SOp-
Tol)2), 1.65–1.66 (mAB, 2H, =CH-CH2), 1.92 (m, 1H,
CHH-CH(SOp-Tol)2), 2.36 (s, 3H, p-Tol), 2.43 (s, 3H,
p-Tol), 3.34 (dd, J=6.3, 5.0 Hz, 1H, CH(SOp-Tol)2),
4.83 (td, J=16.9, 1.0 Hz, 1H, =CHH), 4.92 (dd,
J=10.1, 2.3 Hz, 1H, =CHH), 5.58 (tdd, J=16.9, 10.1,
7.6 Hz, 1H, CH=CH2), 7.25 (s, 4H, arom), 7.36 (d,
J=8.1 Hz, 2H, arom), 7.62 (d, J=8.1 Hz, 2H, arom).
13C NMR (100 MHz, CDCl3) l 20.4 (CH2), 21.6 (p-
Tol), 21.8 (p-Tol), 22.4 (CH2), 26.9 (CH3-C-CH3), 33.0
(CH3-C-CH3), 41.0 (CH2), 46.2 (CH2), 89.3 (CH(SOp-
Tol)2), 117.0 (=CH2), 124.1 (2 CH arom), 125.7 (2 CH
arom), 130.3 (2 CH arom), 130.4 (2 CH arom), 135.5
(CH=CH2), 138.1, 139.4, 141.8, 143.1 (4 C arom). MS
(CI NH3) m/z: 417 (MH+, 60), 277 (M−p-TolSO, 100).
146.1, 147.2, 151.9, 152.6 (2 2 C arom+2 2 vinyl).
ꢀ
ꢀ
3.4.7. 2-Isopropylidene-4,4-dimethyl-cyclopentane carbo-
thioic acid S-p-tolyl ester 12. Chromatography (pen-
tane/Et2O, from 100/0 to 95/5) afforded 12 as a color-
less oil: [h]2D0 −51.0 (c 1.1, CHCl3). IR (neat): 2953,
2925, 2864, 1696, 1493, 1462, 1367, 1070, 1002, 886,
1
806, 776 cm−1. H NMR (400 MHz, CDCl3) l 0.92 (s,
3H, CH3-C-CH3), 1.16 (s, 3H, CH3-C-CH3), 1.71 (s,
3H, =C(CH3)2), 1.72 (s, 3H, =C(CH3)2), 1.85 (dd,
J=12.6, 8.8 Hz, 1H, CHH-CH-CO), 2.00 (dd, J=12.6,
8.8 Hz, 1H, CHH-CH-CO), 2.25 (bs, 2H, =C-CH2),
2.37 (s, 3H, p-Tol), 3.80 (t, J=8.8 Hz, 1H, CH-CO),
7.20 (d, J=8.1 Hz, 2H, arom), 7.28 (d, J=8.1 Hz, 2H,
arom). 13C NMR (100 MHz, CDCl3) l 21.6 (p-Tol),
21.9, 22.1 (=C(CH3)2), 27.5, 28.6 (CH3-C-CH3), 38.8
(CH3-C-CH3), 46.6, 47.1 (CH2), 56.2 (CH-CO), 130.1
(2 CH arom), 134.8 (2 CH arom), 125.3, 129.1, 133.6,
139.4 (2 C arom+2 vinyl), 201.6 (CO). MS (CI NH3)
m/z: 289 (MH+, 100).
Acknowledgements
The authors thank Dr. Carine Guyard-Duhayon

2896
F. Brebion et al. / Tetrahedron: Asymmetry 14 (2003) 2889–2896
(UPMC) for the X-ray structure determination of
10bM, and the Ministe`re de la Recherche for a grant to
F.B.
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J. Am. Chem. Soc. 1999, 121, 11395–11401.
13. Mase, N.; Watanabe, Y.; Toru, T. J. Org. Chem. 1998,
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