Synthesis and characterization of homochiral cholesteryl 1-alkenesulfinate esters

Article abstract of DOI:10.1016/S0957-4166(00)00474-2

A number of α,β-unsaturated sulfinyl chlorides 1 has been separately prepared and treated with (-)-cholesterol under various conditions some of which incorporated chiral amines quinine or quinidine. Some (R_S) vinylic sulfinates could be isolate

Full text of DOI:10.1016/S0957-4166(00)00474-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4843–4852
Synthesis and characterization of homochiral cholesteryl
1-alkenesulfinate esters
Rick R. Strickler and Adrian L. Schwan*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry,
Department of Chemistry and Biochemistry, University of Guelph, Guelph, ON, Canada N1G 2W1
Received 26 September 2000; accepted 13 November 2000
Abstract
A number of a,b-unsaturated sulfinyl chlorides 1 has been separately prepared and treated with
(−)-cholesterol under various conditions some of which incorporated chiral amines quinine or quinidine.
Some (RS) vinylic sulfinates could be isolated in enantiopure form following one or two recrystallizations
of the resulting diastereomeric mixtures of (−)-cholesteryl 1-alkenesulfinates 2. Access to diastereomeri-
cally enriched (SS) vinylic sulfinates (66–75% de) was achieved in three instances. Absolute stereochemical
assignments were made with the assistance of the chiral solvating agent (R)-2,2,2-trifluoro-1-(9-
anthryl)ethanol. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Enantiopure sulfinate esters are an important class of organosulfur compounds. They are
typically employed to prepare enantiopure or enantioenriched sulfoxides using various versions
of the well-known Andersen methodology,1 and the important role that enantiopure sulfoxides
play in asymmetric synthesis is well documented.2 The original Andersen procedure (Scheme 1)
involves treating a sulfinyl chloride with (−)-menthol to generate a diastereomeric mixture of
Scheme 1.
* Corresponding author. E-mail: schwan@chembio.uoguelph
0957-4166/00/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00474-2

4844
R. R. Strickler, A. L. Schwan / Tetrahedron: Asymmetry 11 (2000) 4843–4852
menthyl sulfinate esters which, following their separation, undergo organometallic substitution
to afford enantiomerically pure sulfoxides.
Since the original Andersen method was first introduced several successful adaptations have
been developed. These typically involve the use of other chiral alcohols such as diacetone- -glu-
D
cose (DAG),3 (1R,2S)-(−)-trans-2-phenylcyclohexanol,4 and cholesterol.5 The use of DAG in
combination with a specific choice of base and solvent has been found to be particularly
successful with sulfinate de’s sometimes exceeding 97%.3 Since their introduction, enantiopure
DAG sulfinates have proved particularly useful and have been employed as a source of chiral
2-sulfinyl thioacetamides,6 alkylmethylthiomethyl sulfoxides7 and N-sulfinylimines,8 which in
turn act as a source of other chiral species. The DAG alcohol has also recently been used for
the kinetic resolution of bis-sulfinyl chlorides to synthesize C2-symmetric bis-sulfinate esters.9
Other chiral auxiliaries such as oxazolidinones10 and Oppolzer’s amide11 have been found to
serve as viable substitutes for chiral alcohols.
In many protocols targeting homochiral sulfinate esters, sulfinyl chlorides are used as the
sulfur precursor.12 Generally, the sulfinyl chlorides employed in this chemistry include Me,
p-tolyl, t-Bu, and substituted aryl groups.13 With a practical method established for the
synthesis of 1-alkenesulfinyl chlorides14 it was perceived that application of the Andersen
methodology might provide a useful means for the preparation of homochiral a,b-unsaturated
sulfinate esters. Our first success using 3,3-dimethyl-2-butenesulfinyl chloride was recently
reported in communication form15 and we describe herein the full results addressing the first
synthesis of homochiral 1-alkenesulfinate esters.
2. Results and discussion
2.1. Synthesis of 1-alkenesulfinate esters
The initial experiments of the project were designed to examine a wide range of conditions to
determine which sulfinate esters would provide optimal results. To accomplish this goal an array
of small scale experiments was carried out in which a collection of a,b-unsaturated sulfinyl
chlorides 1 were treated with K2CO3 and various chiral alcohols, chosen mostly on the basis of
established synthetic procedures. These alcohols included: menthol, cholesterol, (DAG),
(1R,2S)-(−)-trans-2-phenylcylcohexanol, borneol, and fenchyl alcohol. From these experiments
three important pieces of information were gathered: (i) use of the established procedure for
1-alkenesulfinate formation14 exhibited very little kinetic stereoselectivity; (ii) the diastereomers
could not be separated using silica gel chromatography; and (iii) with the exception of
cholesterol, all alcohols led to an oily, inseparable mixture of sulfinate diastereomers. On the
basis of the information garnered, it was hoped that recrystallization of the cholesteryl
sulfinates, which consistently presented themselves as a solid mixture of diastereomers, would
provide access to enantiopure 1-alkenesulfinate esters.
Starting with the simplest system, larger scale reactions using ethenesulfinyl chloride 1a were
examined with cholesterol as the chiral auxiliary (Scheme 2). When K2CO3 was used as the base
both low yields and de’s of sulfinate 2a were observed (Table 1, Entry 1).16 The reproducibility
of these results was also poor; possibly resulting from solubility problems encountered with the
cholesterol/K2CO3 suspension at −78°C. Crystallization of the diastereomeric mixture did not
result in any improvement to the de. Hence, various experiments using pyridine, (iPr)2EtN and

R. R. Strickler, A. L. Schwan / Tetrahedron: Asymmetry 11 (2000) 4843–4852
4845
Scheme 2.
Table 1
Preparation of homochiral cholesteryl 1-alkenesulfinate esters (Scheme 2)
Sulfinate product
Conditionsa
Temp. (°C)
Yield (%)/
Recrystallizationc
de (%)b
c
R1
R2 Base
Additiond
De (%)
Yield (%)
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2b
2b
2b
2c
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
K2CO3
−78 to −10
−78
−78 to −20
−78
A
A
B
A
B
A
B
B
A
B
B
B
B
B
B
B
B
B
B
24/13 (SS)
51/35 (RS)
57/47 (RS)
49/25 (SS)
55/22 (SS)
–
–
3
–
6
Quinine
Quinine
Quinidine
Quinidine
K2CO3
Quinine
Quinidine
K2CO3
6 (RS)
–
26 (SS)
–
H
−78 to −20
−78 to −20
−78 to −20
−78 to −20
−78 to −20
−78 to rt
−78 to −20
−78 to rt
−78
−78 to −20
−78 to −20
−78 to −20
−78 to −20
−78 to rt
−78 to rt
–
CO2Me
CO2Me
CO2Me
tBu
tBu
tBu
tBu
tBu
tBu
Ph
63/56 (RS) 100 (RS)
26e
89/6 (SS)
80/12 (RS)
42/0
53/4 (RS)
76/50 (RS)
83/39 (RS)
94/65 (SS)
82/63 (SS)
48/3 (SS)
86 (RS)
20
64 (RS) (100 (RS))
86 (RS) (100 (RS))
92 (RS)
95 (RS)
95 (RS) (100 (RS))
68 (SS)
38 (27)
20 (8)
20
10 2c
11 2c
12 2c
13 2c
14 2c
15 2d
16 2d
17 2d
18 2e
19 2e
K2CO3
Quinine
Quinine
Quinidine
Quinidine
K2CO3
32
42 (36)
46f
70 (SS) (75 (SS))
100 (RS)
31f (12)f
8
Ph
Ph
Ph
Ph
Quinine
Quinidine
73/43 (RS) 100 (RS)
21
14
23 (12)
11
82/43 (SS)
88/10 (RS)
89/9 (SS)
86 (RS)
Cl Quinine
Cl Quinidine
52 (SS)f (94 (SS))f
82 (SS)f
a Solvent was CH2Cl2 unless otherwise noted.
b Sulfinate 2 was obtained as a mixture of diastereomers; de refers to initial de after chromatography.
c Values in parentheses refer to a second recrystallization; crystallization solvent was hexanes unless otherwise
noted.
d Addition mode A: alcohol and base added to sulfinyl chloride solution; addition mode B: sulfinyl chloride
solution added to alcohol and base solution.
e An overall yield of 39% was observed after additional recrystallizations of the mother liquor.
f Recrystallized from acetone.
sparteine were carried out under several different temperature and solvent conditions in an
attempt to optimize both the yield and de of the cholesteryl ethenesulfinate. Unlike the DAG
methodology3 the achiral amine bases did not afford high yields nor high stereoselectivity. It was
suggested, based upon the work reported by Mikolajczyk and co-workers,17 that switching to

4846
R. R. Strickler, A. L. Schwan / Tetrahedron: Asymmetry 11 (2000) 4843–4852
chiral amines such as quinine and quinidine might provide a means to improving both yields
and de’s.
Using the chiral amine base, sulfinyl chloride 1a was again treated with cholesterol to afford
sulfinate 2a (Table 1, Entries 2–4). Under these conditions improvements to both the yield and
de, and moreover, access to either sulfur epimer were achieved. Again, in an effort to achieve
higher de’s and yields, various conditions were manipulated including temperature, solvent and
mode of addition of the reactants. The best yields and de’s were achieved using CH2Cl2 as the
solvent, increasing and then holding the temperature from −78 to −20°C until completion of
the reaction and finally, transferring the crude sulfinyl chloride solution to a pre-cooled
solution of cholesterol and base (Table 1, addition mode B). Unfortunately, all attempts to
isolate either sulfur epimer in an enantiopure form through recrystallization met with little
success.
Application of the quinine or quinidine methodology to sulfinyl chlorides 1b–e offered
improved yields of sulfinates 2b–e, with low to moderate de’s.18 More importantly, enantiopure
(RS) versions of sulfinates 2b–d were obtained after one or two crystallizations from hexanes.19
For sulfinate 2b, regardless of the isomeric enrichment, preferential crystallization of the (RS)
isomer was observed. In the case of sulfinate 2e, preferential crystallization of the (SS) was
observed following one to two crystallizations from hexanes. Access to (SS)-2b was achieved as
follows. Once exhaustive recrystallizations of (RS) has been performed, the mother liquor, now
enriched in the (SS) isomer, was concentrated to afford (SS)-2b (66% de). A single recrystalliza-
tion of the (SS)-2c reaction mixture from acetone provided that material in 70% de. Unfortu-
nately, neither procedure was generally applicable to other substrates.20
The first significant kinetic selectivity found in the formation of enantioenriched sulfinic
esters was by Alcudia et al using the DAG sulfinates.3a Those authors offer a speculative
mechanism whereby an amine base reacts with the sulfinyl chloride to generate a racemic pair
of sulfinyl ammonium diastereomers, which then react with the chiral alcohol to afford
sulfurane intermediates. Those sulfuranes may or may not undergo pseudorotations prior to
releasing the enantiopure sulfinate. The selectivity is believed to arise through differences in
stability between the sulfurane intermediates. The complexity of their suggested mechanism
coupled with unanswered questions concerning the behavior of their proposed sulfuranes
precludes us from applying their mechanism to our compounds. Further, the de’s of the
sulfinates formed in this work are comparatively lower and hence we are in no position at this
time to account for the observed diastereoselectivity in the formation of sulfinates 2.
2.2. Determination of enantiopurity and absolute configuration of 1-alkenesulfinate esters
1
The diastereomeric excesses of the vinylic sulfinates were determined using H NMR spec-
troscopy in C6D6.21 An examination of the vinyl hydrogen peaks indicated the presence of two
isomers, with chemical shift differences between the two peaks sufficient to accurately measure
the de (Fig. 1a,b). Assignment of the absolute configuration was achieved using the chiral
solvating agent (RS)-2,2,2-trifluoro-1-(9-anthryl)ethanol 3. Using a model proposed by Pirkle22
involving two hydrogen bonding interactions (Fig. 2), the chemical shifts of the vinyl hydrogens
can be correlated to the absolute configuration. In complex A the vinyl hydrogens are shielded
by the anthryl group resulting in an upfield shift. Conversely, in complex B no shielding of the

R. R. Strickler, A. L. Schwan / Tetrahedron: Asymmetry 11 (2000) 4843–4852
4847
Figure 1. Spectrum for a-vinyl hydrogen (Ha) peaks for sulfinate 2b as (a) mixture of two isomers in C6D6; (b) isolated
enantiopure in C6D6; (c) two isomers with 1 equiv. of 3; and (d) enantiopure with 1 equiv. of 3
Figure 2. Differential shielding effects of CSA 3 on a vinylic sulfinate
vinyl hydrogens is anticipated and hence the hydrogen resonance remain comparatively
downfield. On this basis the upfield diastereomeric peak represents the (SS) isomer while the
downfield peak represents the (RS) isomer (Fig. 1c,d).
To support further our configurational assignments of 2c, the circular dichroism (CD) spectra
were obtained for both isomers and their Cotton effects (CE) analyzed. The CD curves shown
in Fig. 3 are representative of (RS) and (SS)-2c. For (RS)-2c (Fig. 3a) there is a slight positive CE
around 278 nm followed by a strongly negative CE around 254 nm. This strong CE corresponds
to the umax of 252.0 nm obtained from the UV absorption spectrum of 2c. The CD spectrum of
(SS)-2c (Fig. 3b) exhibits a slight negative CE followed by a strong CE around 254 nm. As the
(SS) isomer is enriched (70% de) and the (RS) isomer is enantiopure the intensity of the CE for
(SS)-2c is not as great. Notice also that the two curves in Fig. 3 are mirror images of each other,
confirming their opposite configurations at sulfur.23
To conclude, the first preparation of enantiopure a,b-unsaturated esters has been achieved.
The capture of 1-alkenesulfinyl chlorides with (−)-cholesterol in the presence of quinine or
quinidine affords the corresponding cholesteryl 1-alkenesulfinate esters with de’s 563%. Follow-

4848
R. R. Strickler, A. L. Schwan / Tetrahedron: Asymmetry 11 (2000) 4843–4852
Fig. 3. Circular dichroism curves for (a) (RS)-2c; (b) (SS)-2c
ing one or two recrystallizations the a,b-unsaturated sulfinate esters can be isolated in enan-
tioenriched or enantiopure form. The yields obtained are significantly greater than those
reported for the cholesterol capture of alkane- or arenesulfinyl chlorides,5 where (−)-cholesterol
has been employed previously. Nucleophilic substitution reactions of the various 1-alkenesul-
finate esters 2 and the anticipated formation of enantioenriched 1-alkenyl sulfoxides is currently
under investigation.
3. Experimental
3.1. General
Melting points are uncorrected. Infrared (IR) spectra were obtained on a Bomen FTIR
1
spectrometer in a solution cell (CH2Cl2 or CDCl3). NMR spectra for H and 13C NMR were
recorded at 400 and 100.6 MHz, respectively, in CDCl3 and C6D6 (for enantiopure or
enantioenriched sulfinates). Mass spectra (MS) were obtained using chemical ionization and
electron impact techniques. CD spectra were recorded on a Jasco J-600 spectropolarimeter.
Diethyl ether and tetrahydrofuran (THF) were freshly distilled from sodium and benzophenone.
Methylene chloride, pyridine and (i-Pr)2EtN were distilled from calcium hydride. Air and water
sensitive reagents were transferred via oven-dried nitrogen-purged syringes. Flash chromatogra-
,
phy was performed on virgin 200–425 mesh Type 60 A silica gel. Analytical thin-layer
chromatography (TLC) was performed using 0.25 mm Merck Kieselgel 60 F254 precoated silica
gel plates. Sulfuryl chloride was purchased from Aldrich as a 1.0 M solution in CH2Cl2. Older
solutions were discarded before complete consumption of their contents. Elemental analyses
were performed by MHW Labs of Phoenix, AZ. With one exception,24 the preparations of the
starting sulfoxides have been reported previously.14
3.2. General method for the oxidative fragmentation of 1-alkenyl (DPM or PMB) sulfoxides and
capture as cholesteryl 1-alkenesulfinate esters
To a solution of 1-alkenyl diphenylmethyl (DPM; or p-methoxybenzyl (PMB)) sulfoxide (1.0
equiv.) in dry CH2Cl2 (5 mL/mmol) at −78°C under N2 was added SO2Cl2 (1.1–1.3 equiv., as a
1 M solution in CH2Cl2) via syringe. The mixture was stirred for 10 minutes then allowed to

R. R. Strickler, A. L. Schwan / Tetrahedron: Asymmetry 11 (2000) 4843–4852
4849
warm to room temperature over 1 hour. After recooling to −78°C and stirring for 10 minutes.
the sulfinyl chloride solution was transferred via syringe to a −78°C solution of cholesterol and
base in CH2Cl2 (7.5 mL/mmol). The reaction mixture was allowed to warm slowly to −20°C and
stirred overnight. When complete by TLC analysis, the reaction mixture was concentrated under
reduced pressure. The vinylic sulfinate product was then isolated using silica gel flash chro-
matography with EtOAc/hexanes as the eluent. Sulfinate ester yields were calculated from the
amount of cholesterol added.
3.2.1. Synthesis of cholesteryl (RS)-ethenesulfinate 2a
The reaction of DPM ethenyl sulfoxide (700 mg, 2.89 mmol) with SO2Cl2 (3.76 mL, 3.76
mmol) yielded sulfinyl chloride, which was transferred to a solution of cholesterol (950 mg, 2.46
mmol) and quinine (1.13 g, 3.47 mmol) in CH2Cl2 at −78°C. The reaction mixture was warmed
to −20°C and stirred overnight. Diastereomerically enriched sulfinate 2a (650 mg, 57%, 42%
[R]S) was isolated as a solid after flash chromatography (two columns, 10% EtOAc/hexanes).
Mp (diastereomerically enriched (RS) sulfinate): 83–84°C; [h]2D5: −26.3 (c 2.16, acetone). 1H NMR
(400 MHz) l: 6.67 (dd, J=16.8 and 10.0 Hz, 1H), 6.11 (d, J=16.8 Hz, 1H), 5.94 (d, J=10.0 Hz,
1H), 5.37 (m 1H), 4.15 (m, 1H), 2.47–2.41 (m, 2H), 1.00 (s, 3H), 0.90 (d, J=6.5 Hz, 3H), 0.85
(d, J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz. 3H), 0.66 (s, 3H), 2.01–1.03 (m, remaining peaks for
cholesteryl skeleton, 26H); 13C NMR (100.6 MHz) l: 143.6, 139.4, 123.9, 123.0, 79.4, 56.6, 56.1,
49.9, 42.2, 40.2 (40.1), 39.6, 39.5, 37.1 (37.1), 36.4, 36.1, 35.7, 31.8, 31.8, 29.9 (29.7), 28.2, 28.0,
24.2, 23.8, 22.8, 22.5, 21.0, 19.2, 18.7, 11.8 (bracketed values are representative of the (SS)
isomer); IR (CH2Cl2) cm−1: 2930, 2907, 2868, 2855, 1606, 1468, 1382, 1375, 1368, 1127, 1027,
1005, 970, 946; MS (CI, NH3) m/z (%): 386 (33), 370 (24), 369 (87), 368 (100). Anal. calcd for
C29H48O2S: C, 75.60; H, 10.50. Found: C, 75.54; H, 10.35.
3.2.2. Synthesis of cholesteryl (SS)-ethenesulfinate 2a
The reaction of DPM ethenyl sulfoxide (976 mg, 4.03 mmol) with SO2Cl2 (5.24 mL, 5.24
mmol) yielded sulfinyl chloride, which was transferred to a solution of cholesterol (1.33 g, 3.43
mmol) and quinidine (1.57 g, 4.84 mmol) in CH2Cl2 at −78°C. The reaction mixture was warmed
to −20°C and stirred overnight. Diastereomerically enriched sulfinate 2a (658 mg, 42%, 17% (SS)
was isolated as a solid after flash chromatography (two columns, 10% EtOAc/hexanes). Mp
(diastereomerically enriched (SS) sulfinate): 81–83°C; [h]2D5: −18.2 (c 2.42, acetone).
3.2.3. Synthesis of cholesteryl (RS)-(E)-2-carbomethoxyethenesulfinate 2b
The reaction of PMB (E)-2-carbomethoxyethenyl sulfoxide (721 mg, 2.84 mmol) with SO2Cl2
(3.69 mL, 3.69 mmol) yielded sulfinyl chloride, which was transferred to a solution of cholesterol
(933 mg, 2.41 mmol) and quinidine (1.11 g, 3.41 mmol) in CH2Cl2 at −78°C. The reaction
mixture was warmed to −20°C and stirred for several hours. Diastereomerically enriched
sulfinate 2b (1.01 g, 81%, 12% (RS)) was isolated as a solid after flash chromatography (3–5%
EtOAc/hexanes). Following crystallization from hexanes the (RS) sulfinate was isolated in a 38%
yield (64% (RS)). Following a second crystallization from hexanes the enantiopure (RS) sulfinate
was obtained in a 27% yield. Mp (enantiopure (RS) sulfinate): 130–132°C; [h]2D5: −25.6 (c 1.06,
1
acetone). H NMR (400 MHz) l: 7.44 (d, J=15.4 Hz, 1H), 6.61 (d, J=15.4 Hz, 1H), 5.38 (m,
1H), 4.81 (m, 1H), 3.82 (s, 3H), 2.42 (m, 2H), 1.00 (s, 3H), 0.91 (d, J=6.4 Hz, 3H), 0.86 (d,
J=6.4 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H), 0.67 (s, 3H), 2.05–0.85 (m, remaining peaks for
cholesteryl skeleton, 26H); 13C NMR (100.6 MHz) l: 164.3, 149.7, 139.1, 128.0, 123.3, 80.6,

4850
R. R. Strickler, A. L. Schwan / Tetrahedron: Asymmetry 11 (2000) 4843–4852
56.6, 56.1, 52.5, 49.9, 42.3, 40.1, 39.7, 39.5, 37.0, 36.4, 36.1, 35.7, 31.8, 31.8, 29.8, 28.2, 28.0,
24.2, 23.8, 22.8, 22.5, 19.3, 18.7, 12.5; IR (CDCl3) cm−1: 3054, 2953, 2865, 1729, 1617, 1467,
1439, 1384, 1371, 1294, 1269, 1222, 1137, 1120, 1027, 994, 971; MS (CI, NH3) m/z (%): 386 (23),
371 (29), 370 (100), 368 (19), 135 (12), 119 (11), 103 (23), 87 (13), 65 (18). Anal. calcd for
C31H50O4S: C, 71.77; H, 9.71. Found: C, 71.50; H, 9.48.
3.2.4. Synthesis of cholesteryl (SS)-(E)-2-carbomethoxyethenesulfinate 2b
After multiple crystallizations from hexanes the (SS) sulfinate was isolated diastereomerically
enriched (66% de). Mp (diastereomerically enriched (SS) sulfinate): 108–110°C; [h]2D5: −11.8 (c
1.36, acetone).
3.2.5. Synthesis of cholesteryl (RS)-(E)-3,3-dimethylbutenesulfinate 2c
The reaction of DPM (E)-(3,3-dimethyl-1-butenyl) sulfoxide (1.12 g, 3.75 mmol) with SO2Cl2
(4.9 mL, 4.88 mmol) yielded sulfinyl chloride, which was transferred to a solution of cholesterol
(1.24 g, 3.19 mmol) and quinine (1.22 g, 3.75 mmol) in CH2Cl2 at −78°C. The reaction mixture
was warmed to rt and stirred overnight. Diastereomerically enriched sulfinate 2c (1.36 g, 83%,
39% de (RS)) was isolated as a solid after flash chromatography (3–5% EtOAc/hexanes).
Following crystallization from hexanes, the enantiopure (RS) sulfinate was isolated in a 42%
yield (89% (RS)). Following a second crystallization from hexanes the (RS) sulfinate was
obtained diastereomerically pure in a 36% yield. Mp (enantiopure (RS) sulfinate): 153–154°C;
1
[h]2D5: −23.2 (c 1.33, CHCl3). H NMR (400 MHz): l: 6.48 (d, J=15.7 Hz, 1H), 6.22 (d, J=15.7
Hz, 1H), 5.37 (m, 1H), 4.14 (m, 1H), 2.48–2.41 (m, 2H), 1.10 (s, 9H), 1.01 (s, 3H), 0.91 (d,
J=6.5 Hz, 3H), 0.87 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H), 0.67 (s, 3H), 0.85–2.02
(remaining peaks for cholesteryl skeleton, 26H); 13C NMR (100.6 MHz) l: 152.0, 139.6, 131.8,
122.8, 78.7, 56.6, 56.1, 49.9, 42.3, 40.3, 39.7, 39.5, 37.2, 36.5, 36.2, 35.8, 34.0, 31.9, 31.8, 29.7,
28.7, 28.2, 28.0, 24.3, 23.8, 22.8, 22.5, 21.0, 19.3, 18.7, 11.8; IR (CH2Cl2) cm−1: 3041, 2944, 2898,
1667, 1623, 1465, 1367, 1129, 1115, 996, 976; MS (CI, NH3) m/z (%): 516 (M+, 1), 386 (8), 371
(29), 370 (100), 369 (7), 368 (22), 354 (7), 149 (10), 133 (8), 131 (5), 115 (8), 83 (2), 57 (12). Anal.
calcd for: C33H56O2S: C, 76.68; H, 10.92. Found: C, 76.85; H, 10.68.
3.2.6. Synthesis of cholesteryl (SS)-(E)-3,3-dimethylbutenesulfinate 2c
The reaction of DPM (E)-(3,3-dimethyl-1-butenyl) sulfoxide (902 mg, 3.03 mmol) with SO2Cl2
(3.63 mL, 3.63 mmol) yielded sulfinyl chloride, which was transferred to a solution of cholesterol
(994 mg, 2.57 mmol) and quinidine (1.18 g, 3.63 mmol) in CH2Cl2 at −78°C. The reaction
mixture was warmed to −20°C and stirred overnight. Diastereomerically enriched sulfinate 2c
(1.19 g, 82%, 63% de (SS)) was isolated as a solid after flash chromatography (3–5% EtOAc/hex-
anes). Following crystallization from acetone the (SS) sulfinate was isolated in a 31% yield (70%
(SS)). Following a second crystallization from acetone the diastereomerically enriched (SS)
sulfinate was isolated in a 12% yield (75% de (SS)). Mp (diastereomerically enriched 70% (SS)):
130–132°C; [h]2D5: −16.6 (c 1.14, CHCl3).
3.2.7. Synthesis of cholesteryl (RS)-(E)-2-phenylethenesulfinate 2d
The reaction of DPM (E)-2-phenylethenyl sulfoxide (457 mg, 1.68 mmol) with SO2Cl2 (2.02
mL, 2.02 mmol) yielded sulfinyl chloride, which was transferred to a solution of cholesterol (552
mg, 1.43 mmol) and quinine (654 mg, 2.02 mmol) in CH2Cl2 at −78°C. The reaction mixture was
warmed to −20°C and stirred overnight. Diastereomerically enriched sulfinate 2d (562 mg, 73%,

R. R. Strickler, A. L. Schwan / Tetrahedron: Asymmetry 11 (2000) 4843–4852
4851
43% (RS)) was isolated as a solid after flash chromatography (3–5% EtOAc/hexanes). Following
crystallization from hexanes the enantiopure (RS) sulfinate was isolated in a 21% yield (100%
(RS)). Mp (enantiopure (RS) sulfinate): 158–160°C; [h]2D5: +14.3 (c 2.65, CHCl3). H NMR (400
1
MHz) l: 7.51–7.49 (m, 2H), 7.42–7.38 (m, 3H), 7.27 (d, J=16.0 Hz, 1H), 6.92 (d, J=16.0 Hz,
1H), 5.37 (m, 1H), 4.21 (m, 1H), 2.51–2.45 (m, 2H), 1.01 (s, 3H), 0.91 (d, J=6.6 Hz, 3H), 0.87
(d, J=6.6 Hz, 3H), 0.86 (d, J=6.6 Hz, 3H), 0.67 (s, 3H), 2.02–1.03 (m, remaining peaks for
cholesteryl skeleton, 26H); 13C NMR (100.6 MHz) l: 139.5, 138.5, 133.4, 133.2, 130.2, 218.9,
128.0, 123.0, 56.6, 56.1, 49.9, 42.3, 39.7, 39.5, 37.1, 36.5, 36.1, 35.8, 31.9, 31.8, 29.8, 28.2, 28.0,
24.2, 23.8, 22.8, 22.5, 21.0, 19.2, 18.7, 11.8; IR (CH2Cl2) cm−1: 3050, 2911, 2909, 2869, 2855,
1614, 1124, 973, 946; MS (EI) m/z (%): 369 (2), 119 (12), 118 (24), 91 (38), 79 (16), 76 (13), 59
(38), 58 (62), 43 (100), 42 (15); MS (positive ion ESI): 537. Anal. calcd for C35H52O2S: C, 78.30;
H, 9.76. Found: C, 78.19; H, 9.53.
3.2.8. Synthesis of cholesteryl (SS)-(Z)-2-chloro-2-phenylethenesulfinate 2e
The reaction of (Z)-2-chloro-2-phenylethenyl-2-(trimethylsilyl)ethyl sulfoxide24 (551 mg, 1.92
mmol) with SO2Cl2 (2.31 mL, 2.31 mmol) yielded sulfinyl chloride, which was transferred to a
solution of cholesterol (632 mg, 1.63 mmol) and quinidine (749 mg, 2.31 mmol) in CH2Cl2 at
−78°C. The reaction mixture was warmed to rt and stirred overnight. Diastereomerically
enriched sulfinate 2e (823 mg, 88%, 10% (RS)) was isolated as a solid after flash chromatography
(3–5% EtOAc/hexanes). Following crystallization from hexanes the (SS) sulfinate was isolated in
a 23% yield (52% (SS)). Following a second crystallization from hexanes the diastereomerically
enriched (SS) sulfinate was isolated in a 12% yield (94% (SS)). Mp (diastereomerically enriched
1
(SS) sulfinate): 141–142°C; [h]2D5: −43.6 (c 2.22, CHCl3). H NMR (400 MHz) l: 7.47–7.43 (m,
3H), 7.42–7.37 (m, 2H), 7.14 (s, 1H), 5.27 (m, 1H), 4.06 (m, 1H), 0.93 (s, 3H), 0.90 (d, J=6.8
Hz, 3H), 0.86 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.8 Hz, 3H), 0.65 (s, 3H), 2.20–0.69 (m, remaining
peaks for cholesteryl skeleton, 28H); 13C NMR (100.6 MHz) l: 147.9, 139.2, 129.7, 129.2, 128.9,
126.6, 123.0, 80.5, 56.6, 56.0, 49.8, 42.2, 39.7, 39.6, 39.4, 37.0, 36.4, 36.1, 35.7, 31.8, 31.7, 29.6,
28.2, 28.0, 24.2, 23.8, 22.8, 22.5, 20.9, 19.1, 18.7, 11.8; IR (CH2Cl2) cm−1: 3062, 2943, 2868, 2852,
1490, 1467, 1444, 1382, 1367, 1136, 992. Anal. calcd for C35H51ClSO2: C, 73.58; H, 9.00. Found:
C, 73.63; H, 8.88.
Acknowledgements
The authors gratefully acknowledge the assistance of Professor Rick Yada and Dr. Massimo
Marcone for instrument use and instruction pertaining to acquisition of the circular dichroism
spectra. The authors would also like to thank the Petroleum Research Fund, administered by
the American Chemical Society, for generously funding this research. RRS thanks the Natural
Sciences and Engineering Research Council of Canada and the Ontario government for
graduate scholarships.
References
1. (a) Andersen, K. K. Tetrahedron Lett. 1962, 93; (b) Andersen, K. K.; Gaffield, W.; Papanikolaou, N. E.; Foley,
J. W.; Perkins, R. I. J. Am. Chem. Soc. 1964, 86, 5637.

4852
R. R. Strickler, A. L. Schwan / Tetrahedron: Asymmetry 11 (2000) 4843–4852
2. (a) Solladie´, G. Synthesis 1981, 185; (b) Walker, A. J. Tetrahedron: Asymmetry 1992, 3, 961; (c) Carren˜o, M. C.
Chem. Rev. 1995, 95, 1717.
3. (a) Ferna´ndez, I.; Khiar, N.; Llera, J. M.; Alcudia, F. J. Org. Chem. 1992, 57, 6789; (b) Llera, J. M.; Ferna´ndez,
I.; Alcudia, F. Tetrahedron Lett. 1991, 32, 7299; (c) Khiar, N.; Ferna´ndez, I.; Alcudia, F. Tetrahedron Lett. 1994,
35, 5719; (d) Ferna´ndez, I.; Khiar, N.; Roca, A.; Benabra, A.; Alcudia, A.; Espartero, J. L.; Alcudia, F.
Tetrahedron Lett. 1999, 40, 2029.
4. (a) Whitesell, J. K.; Wong, M.-S. J. Org. Chem. 1991, 56, 4552; (b) Whitesell, J. K.; Wong, M.-S. J. Org. Chem.
1994, 59, 597.
5. Andersen, K. K.; Bujnicki, B.; Drabowicz, J.; Mikolajczyk, M.; O’Brien, J. B. J. Org. Chem. 1984, 49, 4070.
6. Alayrac, C.; Nowaczyk, S.; Lemarie´, M.; Metzner, P. Synthesis 1999, 669.
7. Arroyo-Go´mez, Y.; Lo´pez-Sastre, J. A.; Rodr´ıguez-Amo, J. F.; Santos-Garc´ıa, M.; Sanz-Tejedor, M. A. J. Chem.
Soc., Perkin Trans. 1 1994, 2177.
8. Garcia-Ruano, J. L.; Ferna´ndez, I.; del Prado Catalina, M.; Alcudia Cruz, A. Tetrahedron: Asymmetry 1996, 7,
3407.
9. Khiar, N.; Alcudia, F.; Espartero, J.-L.; Rodr´ıguez, L.; Ferna´ndez, I. J. Am. Chem. Soc. 2000, 122, 7598.
10. Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.; Cherry, D. J. Am. Chem. Soc. 1992, 114, 5977.
11. Oppolzer, W.; Froelich, O.; Wiaux-Zamar, C.; Bernardinelli, G. Tetrahedron Lett. 1997, 38, 2825.
12. (a) Schwan, A. L.; Strickler, R. R. Org. Prep. Proc. Int. 1999, 31, 579; (b) Tillet, J. G. The Chemistry of Sulphinic
Acids, Esters and their Derivatives; John Wiley & Sons: Chichester, UK, 1990; p. 577.
13. (a) Imboden, C.; Renaud, P. Tetrahedron: Asymmetry 1999, 10, 1051; (b) Mase, N.; Watanabe, Y.; Ueno, Y.;
Toru, T. J. Org. Chem. 1997, 62, 7794.
14. Schwan, A. L.; Strickler, R. R.; Lear, Y.; Kalin, M. L.; Rietveld, T. E.; Xiang, T.-J.; Brillon, D. J. Org. Chem.
1998, 63, 7825.
15. Strickler, R. R.; Schwan, A. L. Tetrahedron: Asymmetry 1999, 10, 4065.
16. The determination of the sulfinate de and the assignment of the absolute configuration is addressed in a later
section of the paper.
17. Drabowicz, J.; Lededz, S.; Mikolajczyk, M. J. Chem. Soc., Chem. Commun. 1985, 1670.
18. In each case, enrichment of either sulfur epimer was possible depending upon the choice of base. In the
preparation of 2b and 2e the use of quinine afforded access to the (SS) sulfinate while quinidine afforded access
to the (RS) sulfinate. In all other cases quinine afforded the (RS) sulfinate while quinidine afforded the (SS)
sulfinate.
19. Further crystallizations of the recovered mother liquor offered improvements of up to 15% for the overall
recovery of the enantiopure sulfinate esters.
20. It was found that for other sulfinates as the diastereomeric mixture became more enriched in the (SS) isomer its
composition went from being a solid to a semisolid with trace impurities that could not be removed.
21. Gautier, N.; Noiret, N.; Nugier-Chauvin, G.; Patin, H. Tetrahedron: Asymmetry 1997, 8, 501.
22. Pirkle, W. H.; Hoover, D. J. Top. Stereochem. 1982, 13, 263. It should be noted that the mode of complexation
of [R]S-2,2,2-trifluoro-1-(9-anthryl)ethanol with sulfinates differs slightly from its interaction with sulfoxides. The
solvating agent adopts a primary H-bonding interaction with the sulfinyl oxygen lone pair and a secondary
interaction with the sulfur lone pair in sulfoxides. In sulfinate esters, the same primary interaction exists, but the
secondary H-bonding takes place with the alcoholic oxygen of the ester.
23. A Grignard reaction of 2c creating a sulfoxide of known stereochemistry provides additional data confirming the
configuration assigned to 2c, assuming inversion of configuration. See. Ref. 15.
24. The procedure used to prepare this starting sulfoxide will be published elsewhere. See: Schwan, A. L.; Strickler,
R. R.; Dunn-Dufault, R.; Brillon, D. Eur. J. Org. Chem., in press.
.