A concise synthesis of β-sitosterol and other phytosterols

Article abstract of DOI:10.1016/j.steroids.2010.05.016

A convenient synthesis of sidechain-modified phytosterols is achieved via a temporary masking of the stigmasterol 5,6-alkene as an epoxide. Following performance of the desired modification, the alkene is regenerated through a mild deoxygenation. The approach is applied to the syntheses of β-sitosterol and campesterol acetate, and suggests a facile route to the (Z)-isomers of Δ^22-23 phytosterols.

Full text of DOI:10.1016/j.steroids.2010.05.016

Steroids 75 (2010) 879–883
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Steroids
journal homepage: www.elsevier.com/locate/steroids
A concise synthesis of ␤-sitosterol and other phytosterols
Jiliang Hang, Patrick Dussault∗
Department of Chemistry, University of Nebraska-Lincoln, 809 Hamilton Hall, Lincoln, NE 68588-0304, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of sidechain-modified phytosterols is achieved via a temporary masking of the
stigmasterol 5,6-alkene as an epoxide. Following performance of the desired modification, the alkene is
regenerated through a mild deoxygenation. The approach is applied to the syntheses of ␤-sitosterol and
campesterol acetate, and suggests a facile route to the (Z)-isomers of ꢀ22–23 phytosterols.
© 2010 Elsevier Inc. All rights reserved.
Received 25 February 2010
Received in revised form 6 May 2010
Accepted 22 May 2010
Available online 31 May 2010
Keywords:
Sitosterol
Campesterol
Phytosterol
Synthesis
Epoxide
Deoxygenation
1. Introduction
ples of ␤-sitosterol, semipreparative applications were challenging
in terms of removal of sterol methyl ether byproducts.
Phytosterols and their derivatives are widely applied in the food
and cosmetic industries, and have recently received a great deal of
attention as nutraceutical additives [1–3]. Phytosterols have also
attracted attention as inhibitors of sarcoplasmic reticulum calcium
ATPase and potassium ion channels [4,5]. As part of a collaboration
investigating the structural influences on uptake and process-
ing of sterol esters [6], we required semipreparative amounts of
␤-sitosterol. However, ␤-sitosterol is commercially available in
preparative amounts only as mixtures with other phytosterols,
including stigmasterol, campesterol, and/or brassicasterol (Fig. 1);
reported separations are relatively laborious [7,8].
Two routes have been reported for the synthesis of ␤-sitosterol
from stigmasterol, which is available in pure form. The first, selec-
tive hydrogenation of the sidechain ꢀ22–23 alkene [9], was found
to produce ␤-sitosterol contaminated with varying amounts of
recovered stigmasterol as well as the fully saturated stigmastanol
[10]. The second approach, which has been applied to the synthe-
sis of sitosterol and related sterols (Fig. 2), circumvents the need
for selective hydrogenation by protecting the ꢀ5–6 alkene as a
cyclopropyl carbinyl ether [11,12]. Following hydrogenation of the
ꢀ22–23 double bond, solvolysis of the cyclopropane reintroduces
both the C3-alcohol and the ꢀ5–6 alkene. Although we found the
latter approach very useful as a means of obtaining very pure sam-
We now report a new strategy for the synthesis of sidechain-
modified phytosterols based upon protection of the ꢀ5–6 alkene
as an epoxide. The approach is illustrated with syntheses of ␤-
sitosterol and campesterol acetate.
2. Experimental
2.1. General experimental procedures
AlI3 and Cu(MnO4)2 were prepared by literature procedures
[13,14]. All other reagents and solvents were used as supplied com-
mercially, except CH2Cl2 (CaH2) and THF (Na, Ph2CO) which were
distilled from the indicated reagent under an atmosphere of N2.
Melting points are uncorrected. Unless noted, NMR spectra were
acquired at 400 MHz (1H) or 100 MHz (13C) in CDCl3; individual
peaks are reported as: multiplicity, integration, coupling constant
in Hz. IR spectra were recorded as neat films on a ZnSe crystal
with selected absorbances reported in cm−1. Mass spectroscopy
was conducted at the Nebraska Center for Mass Spectrometry.
2.2. Stigmasterol acetate (2)
Stigmasterol acetate was prepared as a white solid (97%, mp
138–140 ◦C) by a variant of the procedure of Wang et al. [15]. Other
physical and spectral data were identical to literature values.
∗
Corresponding author. Tel.: +1 402 472 6951; fax: +1 402 472 9402.
E-mail address: pdussault1@unl.edu (P. Dussault).
0039-128X/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2010.05.016

880
J. Hang, P. Dussault / Steroids 75 (2010) 879–883
2.4. 5˛,6˛- and 5ˇ,6ˇ-Epoxy sitosterol acetate (7a, 7b)
To a solution of the 1:6 mixture of 6a and 6b (1.35 g, 3.0 mmol)
in EtOAc (150 mL) was added 10% Pd/C (0.32 g), and the stirred
reaction mixture was placed under an atmosphere of H2 (balloon)
for 12 h. The reaction mixture was filtered through a Celite pad,
and the filtrate evaporated to furnish white solid (1.28 g, 96%, mp
113–114 ◦C) as a 1:6 mixture of epoxides 7a and 7b [8]. Repeat-
ing this reaction on 1.76 g of 6a/6b afforded 1.75 g (99%) of a 1:6
mixture of 7a and 7b.
2.5. ˇ-Sitosterol acetate (4)
The 1:6 mixture of epoxides 7a and 7b (470 mg, 1.0 mmol)
was dissolved in 2:1 CH3CN/CH2Cl2 (30 mL). Aluminum triiodide
was added (610 mg, 1.5 mmol) and the resulting mixture was
stirred at room temperature for 10 min. The reaction was quenched
with aq. 10% Na2S2O3 (100 mL) and the resulting mixture was
extracted with CH2Cl2 (3× 100 mL). The combined organic layers
were dried over Na2SO4, and the residue from the concentrated fil-
trate was purified by flash chromatography (hexane/EtOAc, 95:5)
to give 360 mg (80%) of 4 as a white solid: mp 111–112 ◦C,
[␣]D = −34.5 (CHCl3, c = 1.0). Other physical data were identical to
values reported in the literature [11]. Repeating this reaction on
1.70 g of 7a/7b afforded 1.40 g (85%) of 4.
Fig. 1. Structural relationship of phytosterols.
2.6. ˇ-Sitosterol (3)
2.3. 5˛,6˛- and 5ˇ,6ˇ-Epoxides of stigmasterol acetate (6a, 6b)
To a solution of ␤-sitosterol acetate (4, 240 mg, 0.47 mmol) in
1:1 CH3OH:CH2Cl2 (30 mL) was added K2CO3 (140 mg, 1.01 mmol).
The reaction mixture was stirred at room temperature for 12 h and
then concentrated under vacuum. The residue was extracted with
30 mL CH2Cl2. The organic layer was washed with 30 mL water
and dried over Na2SO4. The filtered organic layer was concentrated
and the residue was purified through flash chromatography (hex-
ane/EtOAc, 80:20) to give 220 mg (93%) of ␤-sitosterol 3 as a white
solid. Mp 134–135 ◦C, [␣]D = −37.0 (CHCl3, c = 1.0). Elemental anal-
ysis calculated for C29H50O: C 83.60, H 11.96; found: 83.99, 12.15.
Other spectral properties were identical to values reported in the
literature [11]. Repeating this reaction on 1.35 g of 4 afforded 1.20 g
(98%) of beta sitosterol (3).
A mixture of KMnO4 (10 g, 60 mmol) and CuSO4·5H2O (5.0 g,
20 mmol) was finely ground in a mortar and pestle [14]. Water
(0.5 mL) was added, and the slightly wet mixture was transferred to
the reaction flask. To the stirred suspension of this mixture in 25 mL
CH2Cl2 was added stigmasterol acetate (2, 2.12 g, 4.51 mmol), fol-
lowed by t-BuOH (2.5 mL). The reaction was heated to reflux for 1 h
and cooled to room temperature. The reaction mixture was filtered
through a silica pad, which was washed with ether. The residue
obtained after concentration was recrystallized from CH3OH to give
a white solid (1.59 g, 75%) with mp 125–126 ◦C. NMR data indicated
the product was a 1:6 mixture of the ␣- (6a) and ␤- (6b) epoxides
of stigmasterol acetate [14]. Repeating this reaction with 2.23 g of
stigmasterol acetate afforded 1.80 g (78%) of a 1:6 mixture of 6a
and 6b.
2.7. (S)-2,3-Dimethylbutan-1-ol (8)
Approach to 5␣,6␣- and 5␤,6␤-epoxides of stigmasterol
acetate (6a, 6b) via peracid epoxidation: to a 0 ◦C solution of 2
(0.308 g, 0.66 mmol) in CH2Cl2 (20 mL) was added mCPBA (0.170 g,
0.76 mmol). After 4 h at 0 ◦C, the reaction was diluted with sat.
aq. K2CO3 (80 mL) and the aqueous layer was extracted with
CH2Cl2 (3× 50 mL). The combined organic layers were dried over
anhydrous Na2SO4 and the filtrate was concentrated in vacuo.
The residue was purified by flash chromatography (hexane/EtOAc,
90:10) to afford 0.257 g (83%) of a white solid which was a 2.6:1
mixture of ␣- (6a) and ␤-isomers (6b) according to 1H NMR.
(S)-2,3-Dimethylbutan-1-ol 8 was prepared as a colorless liq-
uid (overall yield 60%, [␣]D = 4.4, CHCl3, c = 1.0) by the procedure of
Tietze, affording a product with spectral data identical to literature
values [16].
2.8. (S)-2-(2,3-Dimethylbutylthio)benzothiazole (9)
To a mixture of dimethylbutanol 8 (102 mg, 1.00 mmol), 2-
mercaptobenzothiazole (183 mg, 1.10 mmol) and PPh3 (288 mg,
1.10 mmol) in freshly distilled THF (4 mL) was added diisopropyl
Fig. 2. Selective saturation of cyclopropyl carbinyl ether.

J. Hang, P. Dussault / Steroids 75 (2010) 879–883
881
azodicarboxylate (DIAD, 0.21 mL, 1.10 mmol) dropwise at 0 ◦C
under argon. The reaction was stirred for 3 h at 0 ◦C and then
quenched with water. The aqueous layer was extracted with EtOAc
(3× 10 mL) and the combined organic layers were dried over
anhydrous Na2SO4. The filtered organic layer was concentrated
in vacuo and the residue purified by flash chromatography (hex-
ane/EtOAc, 99:1) to afford thioether 9 (228 mg, 91%) as a light
yellow oil. [␣]D = 42.3 (CHCl3, c = 1.6); IR 2957, 1455, 1426, 1057,
mixture of aldehydes 11a and 11b (∼1:6, 85 mg, 0.22 mmol) was
added in 5 mL of THF. Stirring was continued for 1 h, and reac-
tion was gradually warmed to room temperature. The reaction was
quenched by 15 mL water and extracted with EtOAc (3× 10 mL).
The combined organic layers were dried over anhydrous Na2SO4
and filtered. The residue obtained upon concentration was puri-
fied by flash chromatography (hexane/EtOAc, 95:5) to afford a 1:16
mixture of epoxides 12a and 12b as a white solid (90 mg, 90%),
991, 752 cm−1
;
1H NMR: ı 7.89 (d, J = 8.1, 1H), 7.75 (d, J = 8.1, 1H),
mp 145–147 ◦C. IR: 2950, 2867, 1743, 1368, 1037, 764 cm−1 1H
;
7.42 (t, J = 7.2, 1H), 7.29 (t, J = 7.2, 1H), 3.50 (dd, J = 12.7, 4.8, 1H), 3.18
(dd, J = 12.7, 8.2, 1H), 1.88–1.77 (m, 2H), 1.04 (d, J = 6.7, 3H), 0.99 (d,
J = 6.6, 3H), 0.94 (d, J = 6.6, 3H); 13C NMR: ı 167.75, 153.38, 135.15,
125.99, 124.08, 121.44, 120.91, 38.87, 38.78, 31.62, 20.37, 17.96,
15.29; HRFAB-MS (m/z) [M−H]+ calcd for [C13H18NS2]+: 252.0881,
found: 252.0875.
NMR: ı 5.02 (dd, J = 10.9, 9.9, 2H), 4.83–4.73 (m, 1H), 3.09 (d, J = 2.0,
0.95H, ␤), 2.91 (d, J = 4.4, 0.06, ␣), 2.43–2.33 (m, 1H), 2.21–1.80 (m,
9H), 1.68–0.83 (m, 31H), 0.69 (s, 3H); 13C NMR: ı 170.56, 135.13,
131.22, 71.34, 63.58, 62.52, 56.27, 56.02, 51.02, 42.18, 39.72, 38.32,
38.01, 36.68, 35.04, 34.48, 33.35, 32.43, 29.74, 28.32, 27.20, 24.15,
21.92, 21.34, 20.55, 20.36, 19.94, 18.63, 17.06, 12.06; HRFAB-MS
(m/z) [M−H]+ calcd for [C30H49O3]+: 457.3682, found: 457.3668.
2.9. (S)-2-(2,3-Dimethylbutylsulfonyl)benzothiazole (10)
2.12. 5˛,6˛- and 5ˇ,6ˇ-Epoxides of campesterol acetate (13a,
13b)
A 0 ◦C solution of 9 (183 mg, 0.73 mmol) in EtOH (10 mL) was
oxidized with ammonium heptamolybdate tetrahydrate (1.8 g,
1.46 mmol) and 30% H2O2 (2.5 mL, 21.9 mmol) for 2 h. The mixture
was extracted with EtOAc (3× 10 mL) and the combined organic
extracts were washed with brine (3× 10 mL). The dried organic lay-
ers were filtered and the residue obtained upon concentration was
purified by flash chromatography (hexane/EtOAc, 90:10) to afford
sulfone 10 (177 mg, 86%) as a pale yellow oil. [␣]D = 15.5 (CHCl3,
The mixture of epoxides 12a and 12b (30 mg, 0.065 mmol) was
dissolved in 5 mL EtOAc. 10% Pd/C (7 mg) was added, and the reac-
tion mixture was stirred at room temperature under an atmosphere
of H2 (balloon) for 12 h. The reaction mixture was filtered through a
Celite pad, and the filtrate evaporated to a white solid (28 mg, 94%,
mp 110–111 ◦C) as 1:9 mixture of epoxides 13a and 13b. IR: 2953,
c = 3.4); IR 2961, 1470, 1324, 1140, 1085, 758 cm−1 1H NMR: ı
;
2867, 1729, 1367, 1263, 1043, 784 cm−1 1H NMR: ı 5.01–4.93 (m,
;
8.23 (d, J = 7.9, 1H), 8.03 (d, J = 7.9, 1H), 7.68–7.59 (m, 2H), 3.59
(dd, J = 14.4, 3.5, 1H), 3.31 (dd, J = 14.1, 8.9, 1H), 2.29–2.19 (m, 1H),
1.82–1.73 (m, 1H), 1.10 (d, J = 6.9, 3H), 0.89 (d, J = 6.8, 3H), 0.85
(d, J = 6.9, 3H); 13C NMR: ı 166.66, 152.70, 136.74, 128.00, 127.67,
125.43, 122.38, 58.83, 38.68, 32.47, 19.23, 17.89, 15.93; HRFAB-
MS (m/z) [M−H]+ calcd for [C13H18NO2S2]+: 284.0779, found:
284.0778.
0.15H, ␣), 4.83–4.73 (m, 0.96H, ␤), 3.09 (d, J = 2.1, 0.9H, ␤), 2.90
(d, J = 4.4, 0.1H, ␣), 2.12–1.8 (m, 8H), 1.58–0.77 (m, 37H), 0.65 (s,
3H); 13C NMR: ı 170.54, 71.34, 63.58, 62.51, 56.19, 56.14, 50.97,
42.28, 39.78, 38.81, 38.01, 36.66, 35.82, 35.03, 33.65, 32.47, 32.41,
30.26, 29.73, 28.14, 27.21, 24.18, 21.92, 21.31, 20.19, 18.66, 18.24,
17.03, 15.37, 11.76; HRFAB-MS (m/z) [M−H]+ calcd for [C30H51O3]+:
459.3838, found: 459.3820.
2.10. (3ˇ,5˛,6˛)- and
(3ˇ,5ˇ,6ˇ)-Pregnane-20˛-carboxaldehyde-5,6-epoxy-3-yl
acetate (11a, 11b)
2.13. Campesterol acetate (5)
The mixture of epoxides 13a and 13b (28 mg, 0.061 mmol) was
dissolved in 2:1 CH3CN/CH2Cl2 (3 mL). Aluminum triiodide (37 mg,
0.091 mmol) was added and the resulting mixture was stirred at
room temperature for 40 min. The reaction was quenched with
aq. 10% Na2S2O3 (10 mL) and the resulting mixture was extracted
with CH2Cl2 (3× 10 mL). The combined organic layers were dried
over anhydrous Na2SO4, and the residue from the concentrated fil-
trate was purified by flash chromatography (hexane/EtOAc, 95:5)
to give 24 mg (91%) campesterol acetate (5) as a white solid. Mp
130–131 ◦C, [␣]D = −32 (CHCl3, c = 0.7); IR 2954, 1730, 1367, 1247,
A −78 ◦C solution of 6a, 6b (∼1:6 mixture, 100 mg, 0.21 mmol)
in 10 mL of 50/50 CH2Cl2/MeOH was treated with a gaseous stream
of ozone (2% O3/O2) for 5 min. The solution was purged with pure
oxygen and then solvent was removed under vacuum. The residue
was redissolved in 10 mL of 10/90 H2O/AcOH and treated with zinc
powder (55 mg, 0.84 mmol). The reaction mixture was stirred for
2 h at room temperature and then extracted with 50 mL CH2Cl2. The
organic layer was washed with water (3× 25 mL), then dried over
anhydrous Na2SO4. The filtered organic layer was concentrated
and the residue purified by flash chromatography (hexane/EtOAc,
90:10) to afford a 1:6 mixture of epoxides 11a and 11b as a white
solid (81 mg, 99%), mp 87–8 ◦C. IR: 2950, 1727, 1367, 1262, 1238,
1037, 735 cm−1 1H NMR: ı 5.39 (d, J = 4.8, 1H), 4.66–4.58 (m, 1H),
;
2.33 (d, J = 7.9, 2H), 2.05 (s, 3H), 1.90–1.84 (m, 2H), 1.59–0.78 (m,
38H), 0.68 (s, 3H); 13C NMR: ı 170.56, 139.66, 122.66, 73.99, 56.69,
56.08, 50.02, 42.31, 39.73, 38.84, 38.12, 36.99, 36.59, 35.90, 33.70,
32.43, 31.90, 31.86, 30.27, 28.24, 27.78, 24.29, 21.46, 21.03, 20.22,
19.32, 18.70, 18.26, 15.38, 11.87; HRFAB-MS (m/z) [M−Na]+ calcd
for [C30H50O2Na]+: 465.3709, found: 465.3703. Elemental analysis
calculated for C30H50O2: C 81.20, H 11.38; found: 81.39, 11.39. The
1H NMR data matched that of a literature report [17].
1042, 783 cm−1 1H NMR: ı 9.57 (d, J = 3.3, 0.76H, ␤), 9.55 (d,
;
J = 3.3, 0.16H, ␣), 4.99–4.91 (m, 0.14H, ␣), 4.81–4.73 (m, 0.87H, ␤),
3.09 (d, J = 2.2, 0.88H, ␤), 2.90 (d, J = 4.2, 0.13H, ␣), 2.38–2.31 (m,
1H), 2.13–1.82 (m, 9H), 1.54–0.89 (m, 20H), 0.7 (s, 3H); 13C NMR:
ı 204.95, 170.52, 71.25, 63.41, 62.48, 55.39, 51.05, 50.93, 49.42,
42.89, 39.43, 37.95, 36.67, 35.06, 32.41, 29.74, 27.17, 26.97, 24.54,
21.84, 21.30, 17.03, 13.40, 12.11; HRFAB-MS (m/z) [M−Li]+ calcd
for [C24H36LiO4]+: 395.2774, found: 395.2778.
3. Results and discussion
2.11. (3ˇ,5˛,6˛,22Z)- and
(3ˇ,5ˇ,6ˇ,22Z)-Ergost-5,6-epoxy-22-en-3-yl acetate (12a, 12b)
Our synthesis of ␤-sitosterol (3) is illustrated in Scheme 1. Selec-
tive epoxidation of the ꢀ5–6 alkene of stigmasterol acetate (2)
with copper permanangate formed a 6:1 mixture of the 5␤,6␤-
and 5␣,6␣-epoxides 6b and 6a [14,18]. Hydrogenation over Pd/C
cleanly furnished a 1:6 mixture of sitosterol epoxides 7a and 7b.
Deoxygenation of the saturated epoxides with AlI3 [13] proceeded
To a 78 ◦C solution of sulfone 10 (62 mg, 0.22 mmol) in THF
(5 mL) was dropwise added LiHMDS (0.22 mL, nominally 1 M in
THF, 0.22 mmol). The reaction was stirred for 1 h, whereupon the

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J. Hang, P. Dussault / Steroids 75 (2010) 879–883
Fig. 3. Generality of Z-selective olefination.
earlier (AlI3, 10 min, CH3CN/CH2Cl2) now furnished only 33% of
␤-sitosterol acetate (4), accompanied by a significant amount (esti-
mated >60% by mass) of a more polar product which yellowed
immediately upon exposure to room light. The formation of the
byproduct could be avoided almost completely by allowing the
deoxygenation to proceed for 40 min. Alternatively, the byprod-
uct could be converted to 4 by treatment with additional AlI3. The
results suggest that the deoxygenation of the ␣- and ␤-epoxides
proceeds at very different rates, with the 5␣,6␣ diastereomer (6a)
reacting via the intermediacy of a semistable iodohydrin.
As illustrated in Scheme 2, our strategy also provides a facile
means of preparing other sidechain-modified phytosterols. For
example, ozonolysis of the mixture of 6a/6b furnished an approx-
imately 1:6 mixture of aldehydes 11a and 11b. Julia-Kocienski
olefination, using an enantiomerically pure sulfone (10) derived
from (S)-2,3-dimethylbutanol (8) [16] furnished exclusively alkene
12 [20], corresponding to the monoepoxide of the Z-isomer of
crinosterol [21]. Hydrogenation, followed by deoxygenation of the
epoxide as before, furnished campesterol acetate (5).
The selective formation of Z-alkenes is unusual in Julia couplings
[22] and we investigated the olefination of 11a and 11b with a
known sulfone derived from isobutyl alcohol (Fig. 3) [23]. This reac-
tion also selectively furnished the Z-alkene; the lower selectivity
(2:1) compared with that observed for the synthesis of 12a and
12b may reflect the reduced degree of steric encumbrance in this
model system. The ability to readily prepare Z-isomers of phytos-
terols opens the door to a number of steroid analogs not available
from synthetic routes based upon Claisen rearrangements of C22
allylic alcohols [12].
Scheme 1. Synthesis of sitosterol.
rapidly to furnish a good yield of ␤-sitosteryl acetate 4. Saponi-
fication afforded pure ␤-sitosterol (3), with mp 134–135 ◦C and
[␣]D = −37.0 [8,19].
Epoxidation with the commercially available peracid mCPBA
also gave good selectivity for the ꢀ5–6 alkene, but now pro-
duced a 2.6:1 mixture of stigmasterol oxides favoring the ␣-isomer
(6a). Hydrogenation proceeded uneventfully to furnish the cor-
responding mixture of sitosterol oxides 7a and 7b. However,
attempted deoxygenation under the same conditions as employed
4. Conclusions
The formation of ␤-sitosterol has been achieved in 52% over-
all yield from commercially available stigmasterol using relatively
simple chemistry and via easily purified intermediates. The core
strategy, protection of the ꢀ5–6 alkene as an epoxide, holds poten-
tial for the synthesis of other phytosterols as well as unnatural
analogs.
Acknowledgements
We thank Professor Tim Carr (University of Nebraska-Lincoln,
Department of Nutrition and Health Sciences) for useful discus-
sions. This research was supported by a USDA-NRI competitive
grant (2007-35200-18298). Portions of this work were conducted
in facilities remodeled with support from NIH (RR016544-01). NMR
spectra were acquired, in part, on spectrometers purchased with
NSF support (MRI 0079750, CHE 0091975).
Appendix A. Supplementary data
Supplementary data for this article, consisting of 1H and 13C
NMR spectra for compounds 3–13, can be found in the online ver-
sion, at doi:10.1016/j.steroids.2010.05.016.
Scheme 2. Synthesis of campesterol acetate.

J. Hang, P. Dussault / Steroids 75 (2010) 879–883
883
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