Enantioselective catalytic approach to the C23–C28 subunit of 24α-methyl steroids

Article abstract of DOI:10.1016/j.steroids.2019.05.003

Enantioselective synthesis of C23–C28 subunit of campestane steroids based on catalytic methods is reported. The synthesis was started from (S)-2-isopropyl-4-nitrobutan-1-ol, which is easily accessible by the reaction between isovaleraldehyde and nitroethylene catalyzed by only 2% of (S)-trimethylsilyldiphenylprolinol. Removal of one “extra” carbon from the nitroalcohol was achieved by Ni-catalyzed hydrodecarboxylation of the redox-active ester intermediate. The synthesized C23–C28 fragment was attached to a steroidal core by Julia-Kocienski reaction of a steroidal aldehyde with metallated C23–C28 sulfone. The obtained product of olefination was easily transformed to a precursor of campesterol and (Z)-22-dehydrocampesterol.

Full text of DOI:10.1016/j.steroids.2019.05.003

Accepted Manuscript
Enantioselective catalytic approach to the C23-C28 subunit of 24α-methyl ste-
roids
Viktoryia S. Yakimchyk, Volha V. Kazlova, Alaksiej L. Hurski, Rimma G.
Savchenko, Svetlana A. Kostyleva, Vladimir N. Zhabinskii, Vladimir A.
Khripach
PII:
S0039-128X(19)30094-7
https://doi.org/10.1016/j.steroids.2019.05.003
STE 8410
DOI:
Reference:
Steroids
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 March 2019
4 May 2019
10 May 2019
Please cite this article as: Yakimchyk, V.S., Kazlova, V.V., Hurski, A.L., Savchenko, R.G., Kostyleva, S.A.,
Zhabinskii, V.N., Khripach, V.A., Enantioselective catalytic approach to the C23-C28 subunit of 24α-methyl
steroids, Steroids (2019), doi: https://doi.org/10.1016/j.steroids.2019.05.003
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Enantioselective catalytic approach to the C23-C28 subunit of 24α-
methyl steroids
Viktoryia S. Yakimchyka, Volha V. Kazlovaa, Alaksiej L. Hurskia,*, Rimma G. Savchenkob,
Svetlana A. Kostylevab, Vladimir N. Zhabinskiia, Vladimir A. Khripacha
aInstitute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich str.,
5/2, 220141 Minsk, Belarus
bInstitute of Petrochemistry and Catalysis of Russian Academy of Sciences, prosp. Oktyabrya
141, 450075 Ufa, Russian Federation
Enantioselective synthesis of C23-C28 subunit of campestane steroids based on catalytic methods is
reported. The synthesis was started from (S)-2-isopropyl-4-nitrobutan-1-ol, which is easily accessible by
the reaction between isovaleraldehyde and nitroethylene catalyzed by only 2% of (S)-
trimethylsilyldiphenylprolinol. Removal of one “extra” carbon from the nitroalcohol was achieved by Ni-
catalyzed hydrodecarboxylation of the redox-active ester intermediate. The synthesized C23-C28 fragment
was attached to a steroidal core by Julia-Kocienski reaction of a steroidal aldehyde with metallated C23-
C28 sulfone. The obtained product of olefination was easily transformed to a precursor of campesterol and
(Z)-22-dehydrocampesterol.
Keywords: Michael addition; Decarbonylation; Ni-catalyzed decarboxylation; Campesterol; cis-22-
Dehydrocampesterol.
Abbreviations: DEAD, diethyl azodicarboxylate; DIC, diisopropyl carbodiimide; DMAP, 4-
dimethylaminopyridine; DPPA, diphenylphosphoryl azide; HMDS, hexamethyldisilazane; LiHMDS, lithium
hexamethyldisilazide; NHPI, N-hydroxyphthalimide; PE, petroleum ether; TBDPSCl, tert-butyldiphenylsilyl
chloride
* Corresponding author. E-mail address: ahurski@iboch.by (A. Hurski)

1 Introduction
Steroids bearing a 24α-methyl substituent in the side chain are known as campestanes and
typically they are produced by plants and marine organisms. The most abundant steroid of this
group is campesterol (1), an important component of the plant cell membrane [1] (Fig. 1).
Crinosterol (2) differing from campesterol by the presence of a 22-double bond was found in
marine invertebrates [2]. Several campestanes are remarkable for their potent biological activity.
For instance, brassinolide (3) and related phytohormones regulate biological processes in plants at
low nanomolar concentrations [3, 4]. Ecdysteroid makisterone A (4) is a moulting hormone of the
honey bee, Apis mellifera [5]. Recently, new cytotoxic sterols swinhoeisterols, bearing the
campestane side chain along with a unique rearranged skeleton were isolated from the sponge
Theonella swinhoei [6, 7]. Swinhoeisterol A (5) shows an inhibitory activity (IC50 = 2.9 μM)
against h(p300), a histone acetyltransferase associated with the manifestation of cancer.
OH
28
24
25
21
18
22
20
12
26
17
16
23
11
9
HO
HO
HO
19
H13
H
1
4
H
14
27
2
8H
H
H
15
10
H
H
7
HO
HO
5
O
H
O
3
6
2
crinosterol ( )
1
campesterol ( )
3
brassinolide ( )
OH
OH
OH
HO
HO
HO
H
O
OH
H
H
O
H
5
swinhoeisterol A ( )
4
makisterone A ( )
Fig. 1. Structures of some natural steroids with a campestane side chain
In synthesis of campestanes, the side chain is always constructed synthetically because steroids
bearing a 24α-methyl group are still not available as starting materials in a pure form. Generally,
two strategies are used for the formation of the side chain (Scheme 1). One of them is based on a
sequence of diastereoselective reactions [8-15], which in most cases includes Johnson-Claisen or
Ireland-Claisen reaction of allylic alcohol 7 [8-14] (or similar ones [15]). Alternatively, the target

molecule can be obtained by attaching a chiral side chain to a steroidal core. As far as steroidal
C22 aldehydes 6 are easily accessible, their coupling with C23-C28 fragments is the most
frequently applied method of the convergent synthesis of campestanes.
To prepare C23-C28 units, either modification of the chiral commercial starting material [16-
22] or asymmetric methods of synthesis [23-29] were previously used. Mori reported preparation
of sulfone 17 starting from commercial (R)-(+)-citronellic acid (11) [16]. In our laboratory, the
same sulfone was obtained from chiral Roche esters 12 and 13 [18, 19]. Alkylation of chiral
auxiliary-modified intermediates 14 and 15 was used in synthesis of organomagnesium reagent 18
[30] and benzothiazole derivative 19 [31]. Although these approaches are efficient, they suffer
from an important disadvantage in that they require the use of stoichiometric amounts of a chiral
starting material or an auxiliary, which is not ideal from the standpoint of atom economy.
With the idea of the need of more “green” way to the C23-C28 unit of campestanes, we have
recently developed an asymmetric organocatalytic hydroxymethylation-based method of synthesis
of dithiane 20 [32]. Although the key step in this approach is catalytic and the method is suitable
for preparation of multigram quantities of the product, it is not optimal because the required
amount of the chiral catalyst of 20% is relatively high. A more efficient way to the C23-C28
fragment is still demanded. In this article, we report preparation of subunit 23 based on
dehomologation of optically pure nitro alcohol 22, which is available via an asymmetric reaction
catalyzed by only 2% of chiral organocatalyst 21 and proceeding with more than 99%
enantioselectivity [33].

Johnson-Claisen or
Ireland-Claisen
rearrangement-based
approach
OH
Y
O
X
H
H
X
9
7
H
6
Y
Z
8
10
H
H
R1 R2
O
OH
N
H
+
N
OH
O
O
MeO
Ph
MeO2C
CO2H
O
16
Ph
1
2
14
Ph
12
13
: R =Me, R =H
15
11
1
2
: R =H, R =Me
Ph
OTMS
N
H
21
20 mol %
O O
S
O O
S
N
BrMg
S
Ph
S
S
18
17
19
20
This work:
Ph
Ph
OTMS
N
NO2
NO2
O O
S
H
21
+
2 mol %
N
HO
O
N
N
then NaBH4
Ref. [33]
N
22
Ph
16
23
Scheme 1. Approaches to the synthesis of campestane side chains 9, 10 and
C23-C28 fragments 17-20, 23

2 Experimental
2.1 General
Melting points were measured using a Boetius apparatus and are uncorrected. 1H and 13C NMR spectra
were obtained using a Bruker AVANCE 500 (Bruker Biospin, Rheinstetten, Germany) spectrometer
operating at 500.13 MHz for 1H and 125.77 MHz for 13C. Chemical shift values are given in δ (ppm) relative
to the residual solvent peaks: δH 7.26 and δC 77.16 for CDCl3, and coupling constants are reported in Hz.
COSY, HSQC, HMBC, and NOESY experiments were carried out with the use of the standard Bruker
program package. HRMS/MS-spectra were acquired with an Agilent 6550 iFunnel QTOF (Agilent
Technologies, USA). Chemicals were purchased from Aldrich and Fluka and used as received. Optical
rotations were measured with an Autopol III polarimeter. Solvents were dried and freshly distilled
according to standard procedures [34]. (S)-2-Isopropyl-4-nitrobutan-1-ol (22) was prepared in a 78% yield
from 3-methylbutanal (16) and nitroethylene in the presence of 2% of (S)-2-
(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine (21) and 20% of m-nitrobenzoic acid according to the
procedure described in [33]. All reactions were performed under positive argon pressure. TLC was
performed on precoated aluminum backed TLC sheets (silica gel 60 F254) and visualized by spraying with
phosphomolybdic acid followed by heating. Column chromatography was conducted with Merck silica gel
60: 70–230 mesh.
2.2 Chemical synthesis
2.2.1 (S)-tert-Butyl(2-isopropyl-4-nitrobutoxy)diphenylsilane (22a)
A solution of (S)-2-isopropyl-4-nitrobutan-1-ol (22) (6.0 g, 37.2 mmol) and imidazole (10.1 g,
148 mmol) in DMF (75 mL) was kept under argon at ambient temperature for 12 h. Then it was
o
cooled to 0 C and treated with water (75 mL). The mixture was extracted with EtOAc (3  25
mL). The combined organic layers were dried over Na2SO4, and evaporated in vacuo. The residue
was chromatographed on SiO2 (PE-EtOAc, 100:0  94:6) to give 22a (10.2 g, 68%) as a colorless
oily liquid. [훼]퐷20 = -2.09 (c 1.43, CHCl3). 1H NMR (CDCl3): δ 7.67 – 7.63 (m, 4H), 7.47 – 7.38

(m, 6H), 4.48 – 4.33 (m, 2H), 3.64 (dd, J = 10.5, 4.6 Hz, 1H), 3.59 (dd, J = 10.5, 6.5 Hz, 1H), 2.20
– 2.10 (m, 1H), 2.07 – 1.98 (m, 1H), 1.81 – 1.71 (m, 1H), 1.45 – 1.36 (tt, J = 9.4, 4.8 Hz, 1H), 0.86
13
(d, J = 7.0 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H). C NMR (CDCl3): δ 135.7 (x 4), 133.5, 133.4,
129.97, 129.95, 127.9 (x 4), 74.9, 64.8, 44.0, 28.9, 27.3, 27.0 (x 3), 20.0, 19.5, 19.3. HRMS (ESI+):
calcd for C23H33NNaO3Si [M+Na]+ 422.2122, found 422.2119.
2.2.2 (S)-3-(((tert-Butyldiphenylsilyl)oxy)methyl)-4-methylpentanal (24)
A mixture of 22a (304 mg, 0.76 mmol), K2CO3 (168 mg, 1.22 mmol) and methanol (5.4 mL) was stirred
o
at 0 C under argon for 1 h. After this, a freshly prepared solution of KMnO4 (80.6 mg, 0.51 mmol) and
MgSO4 (67.6 mg, 0.56 mmol) in water (3.2 mL) was added dropwise. Stirring was continued at 0 oC for 3
h, then the mixture was filtered through a pad of silica gel and evaporated. The residue was dissolved in
EtOAc, washed with water until neutral and dried (Na2SO4). Solvents were evaporated and the residue
was chromatographed on SiO2 (PE-EtOAc, 95:5) to give aldehyde 24 (234 mg, 84%) as a colorless oily liquid.
1
[훼]퐷20 = 5.01 (c 1.13, CHCl3). H NMR (CDCl3): δ 9.79 (dd, J = 2.6, 2.0 Hz, 1H), 7.69 – 7.62 (m, 4H), 7.47 –
7.37 (m, 6H), 3.67 (dd, J = 10.2, 5.0 Hz, 1H), 3.55 (dd, J = 10.2, 7.7 Hz, 1H), 2.47 (ddd, J = 16.3, 8.1, 2.8 Hz,
1H), 2.40 (ddd, J = 16.3, 4.9, 1.8 Hz, 1H), 2.15 – 2.07 (m, 1H), 1.82 – 1.72 (m, J = 13.6, 6.8 Hz, 1H), 1.05 (s,
9H), 0.85 (d, J = 6.9 Hz, 3H), 0.82 (d, J = 6.9 Hz, 3H). 13C NMR (CDCl3): δ 203.2, 135.7 (x 4), 133.5 (x 2), 129.8
(x 2), 127.8 (x 4), 65.4, 43.9, 42.4, 28.6, 26.9 (x 3), 20.3, 19.5, 19.3. HRMS (ESI+): calcd for C23H32NaO2Si
[M+Na]+ 391.2064, found 391.2058.
2.2.3 (S)-tert-Butyl(2,3-dimethylbutoxy)diphenylsilane (25)
A solution of the aldehyde 24 (729 mg, 1.99 mmol) and (Ph3P)3RhCl (184 mg, 0.20 mmol) in toluene
was thoroughly purged with argon for 15 min. The temperature was brought up to 100 oC, after which a
solution of DPPA (546 mg, 1.99 mmol) in toluene (2.2 mL) was added over 4 h. The reaction mixture was
stirred for another 1 h, then the solvent was evaporated in vacuo, and the residue was chromatographed
on SiO2 (PE-EtOAc, 100:0  99:1) to give silane 25 (558 mg, 83%) as a colorless oily liquid. [훼]퐷20 = 4.14 (c
1.06, CHCl3). 1H NMR (CDCl3): δ 7.72 – 7.68 (m, 4H), 7.46 – 7.38 (m, 6H), 3.60 (dd, J = 9.9, 6.0 Hz, 1H), 3.51
(dd, J = 9.9, 6.6 Hz, 1H), 1.84 – 1.74 (m, 1H), 1.57 (dp, J = 13.0, 6.7 Hz, 1H), 1.08 (s, 9H), 0.89 (d, J = 4.0 Hz,

3H), 0.88 (d, J = 4.0 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H). 13C NMR (CDCl3): δ 13C NMR (CDCl3) δ 135.8 (x 4), 134.3,
134.3, 129.6 (x 2), 127.7 (x 4), 67.5, 41.6, 28.9, 27.0 (x 3), 20.9, 19.5, 18.3, 12.9. HRMS (APCI): calcd for
C22H33OSi [M+H]+ 341.2295, found 341.2294.
2.2.4 (S)-2-Isopropyl-4-nitrobutyl benzoate (26)
To a solution of (S)-2-isopropyl-4-nitrobutan-1-ol (22) (10.3 g, 64 mmol) in pyridine (64 mL), DMAP (78
mg, 0.64 mmol) and benzoyl chloride (11.0 mL, 95 mmol) were added at 0 °C. The mixture was stirred for
1 h, then the cooling bath was removed and stirring was continued at ambient temperature for additional
12 h. After addition of water (250 mL) and separation of the organic layer, the water phase was extracted
with CH2Cl2 (3 x 60 mL). The combined organic layers were washed with 5% HCl, dried over Na2SO4, and
evaporated under reduced pressure. The residue was chromatographed on SiO2 (PE-EtOAc, 100:0  92:8)
to give nitro benzoate 26 (13.1 g, 78 %) as viscous yellow oil. [훼]퐷20 = -6.95 (c 0.777, CHCl3). 1H NMR (CDCl3):
δ 8.05 – 7.99 (m, 2H), 7.62 – 7.53 (m, 1H), 7.46 (t, J = 7.8 Hz, 2H), 4.58 – 4.47 (m, 2H), 4.41 (dd, J = 11.5,
4.7 Hz, 1H), 4.24 (dd, J = 11.5, 6.5 Hz, 1H), 2.25 (dtd, J = 14.7, 7.8, 4.7 Hz, 1H), 2.13 – 2.02 (m, 1H), 1.88
(pd, J = 7.0, 5.0 Hz, 1H), 1.76 (ddq, J = 9.5, 6.5, 4.8 Hz, 1H), 1.01 (t, J = 7.2 Hz, 6H). 13C NMR (CDCl3): δ 166.6,
133.3, 130.0, 129.7 (x 2), 128.7 (x 2), 74.4, 65.6, 40.9, 29.3, 27.3, 19.7, 19.4. HRMS (APCI): calcd for
C14H20NO4 [M+H]+ 266.1387, found 266.1342.
2.2.5 (S)-3-((Benzoyloxy)methyl)-4-methylpentanoic acid (27)
A mixture of nitro benzoate 26 (12.91 g, 48.7 mmol), NaNO2 (14.0 g, 203 mmol), AcOH (28
mL) and DMSO (97 mL) was stirred at 50 °C for 4 h. Then it was cooled to ambient temperature
and diluted with 10% HCl. The product was extracted with EtOAc (5 x 30 mL). The combined
extracts were washed with water, dried over Na2SO4 and concentrated. The residue was
chromatographed on SiO2 (PE-EtOAc, 100:0  90:10) to give 9.82 g (80%) of acid 27 as viscous
yellow oil. [훼]퐷20 = -7.66 (c 0.783, CHCl3). 1H NMR (CDCl3): δ 8.01 (d, J = 7.2 Hz, 2H), 7.53 (t,
J = 7.3 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 4.43 (dd, J = 11.1, 5.0 Hz, 1H), 4.25 (dd, J = 11.1, 7.3
Hz, 1H), 2.50 (dd, J = 15.9, 5.2 Hz, 1H), 2.41 (dd, J = 15.9, 8.2 Hz, 1H), 2.34 – 2.25 (m, 1H), 1.89
(dd, J = 12.2, 6.6 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H). 13C NMR (126 MHz,

CDCl3) δ 179.00, 166.67, 133.11, 130.24, 129.70 (x 2), 128.51 (x 2), 66.00, 40.43, 34.15, 29.04,
19.71, 19.65. HRMS (ESI+): calcd for C14H18NaO4 [M+Na]+ 273.1097, found 273.1101.
2.2.6 (S)-4-((1,3-Dioxoisoindolin-2-yl)oxy)-2-isopropyl-4-oxobutyl benzoate (28)
Diisopropyl carbodiimide (4.7 mL, 30 mmol) was added to a cooled to 0 °C mixture of the acid
27 (6.26 g, 25 mmol), N-hydroxyphthalimide (4.5 g, 27.6 mmol), DMAP (150 mg, 1.2 mmol) and
dry CH2Cl2 (125 mL). The cooling bath was removed and the mixture was stirred at ambient
temperature for 3 h. Then solvents were evaporated under reduced pressure and the residue was
chromatographed on SiO2 (PE-EtOAc, 100:0  80:20) to give NHPI ester 28 (9.69 g, 98%) as
20
1
viscous yellow oil. [훼]퐷 = -11.29 (c 0.797, CHCl3). H NMR (CDCl3): δ 8.07 – 8.03 (m, 2H),
7.91 – 7.85 (m, 2H), 7.79 (dd, J = 5.5, 3.1 Hz, 2H), 7.59 – 7.53 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H),
7.26 (s, 1H), 4.51 (dd, J = 11.4, 5.1 Hz, 1H), 4.37 (dd, J = 11.4, 6.8 Hz, 1H), 2.84 (d, J = 6.7 Hz,
2H), 2.43 – 2.34 (m, 1H), 2.01 (ddd, J = 13.8, 12.1, 6.4 Hz, 1H), 1.07 (d, J = 6.8 Hz, 3H), 1.05 (d,
J = 6.8 Hz, 3H). 13C NMR (CDCl3): δ 169.2 (x 2), 166.6, 162.0, 134.9 (x 2), 133.2, 130.2, 129.8
(x 2), 129.1, 128.6 (x 2), 124.1 (x 2), 65.1, 40.9, 31.2, 29.0, 19.9, 19.5. HRMS (ESI+): calcd for
C22H21NO6 [M+Na]+ 418.1259, found 418.1261.
2.2.7 (S)-2,3-Dimethylbutyl benzoate (29)
A flask was charged with NiCl26H2O (0.051 g, 0.215 mmol) and 4,7-diphenyl-1,10-
phenanthroline (0.142 g, 0.427 mmol), and the apparatus was purged with Ar. DMF (2.2 mL,
anhydrous) was added, and the mixture was stirred for 10 minutes. THF (9 mL) and i-PrOH (1.1
mL) were then added, followed by a solution of 28 (0.841 g, 2.127 mmol) in 1.6 ml of THF and
Zn powder (0.070 g, 1.070 mmol). Immediately following the addition of the Zn powder, PhSiH3
(neat, 0.786 mL, 6.381 mmol) was added dropwise. Upon completion of the addition of PhSiH3,
the reaction mixture was placed in a preheated 40 °C oil bath and stirred for 1 hour. After 1 hour
the mixture was allowed to cool to ambient temperature and 30 ml of half-saturated solution of
NH4Cl was added. The organic layer was separated, the aqueous was extracted with EtOAc (4 x

10 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced
pressure. The residue was chromatographed on SiO2 (PE-EtOAc, 100:0  98:2) to give ester 29
(206 mg, 47 %) as a colorless oil. [훼]퐷20 = 6.55 (c 0.327, CH2Cl2). 1H NMR (CDCl3): δ 8.08 – 8.01
(m, 2H), 7.59 – 7.52 (m, 1H), 7.48 – 7.41 (m, 2H), 4.29 (dd, J = 10.8, 5.8 Hz, 1H), 4.16 (dd, J =
10.8, 6.8 Hz, 1H), 1.88 – 1.72 (m, 2H), (0.98 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H)), 0.92
(d, J = 6.6 Hz, 3H). 13C NMR (CDCl3): δ 166.9, 132.9, 130.7, 129.7 (x 2), 128.5 (x 2), 68.5, 38.4,
29.7, 20.5, 18.6, 13.4.
2.2.8 (S)-5-((2,3-Dimethylbutyl)thio)-1-phenyl-1H-tetrazole (32)
A mixture of the benzoate 29 (1.070 g, 5.19 mmol), KOH (436 mg, 7.77 mmol) and MeOH (3
mL) was stirred at 50 °C for 3 h. After cooling to ambient temperature, the mixture was diluted
with water (9 mL) and extracted with a mixture Et2O-pentane (1:1, 4 x 5 mL). The combined
organic phases were dried over Na2SO4 and the resulting solution was concentrated by distillation
under normal pressure. The residue containing (S)-2,3-dimethylbutan-1-ol (30) was diluted with
THF (50 mL), and then triphenylphosphine (1.496 g, 5.70 mmol) and 1-phenyl-1H-tetrazol-5-thiol
(31) (1.016 g, 5.70 mmol) were added. The mixture was cooled to 0 °C, and then a solution of
DEAD in toluene (40 wt %, 2.6 mL, 5.97 mmol) was added dropwise. After the entire reagent has
been added, the reaction mixture was warmed to room temperature and stirred for 12 h. Then it
was concentrated under reduced pressure, the resulting residue was diluted with a mixture of
petroleum ether and ethyl acetate (9:1, 90 mL). The precipitate was filtered off and the resulting
filtrate was concentrated under reduced pressure. The residue was purified by column
chromatography on SiO2 (PE-EtOAc, 100:0  95:5) to give phenyl tetrazole 32 (1.292 g, 95%
based on 29) as a colorless oil. [훼]퐷20 = 16.33 (c 0.307, CH2Cl2). 1H NMR (500 MHz, CDCl3) δ
7.60 – 7.49 (m, 5H), 3.51 (dd, J = 12.6, 5.3 Hz, 1H), 3.22 (dd, J = 12.6, 8.3 Hz, 1H), 1.84 – 1.71
13
(m, 2H), 0.97 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H). C NMR
(CDCl3): δ 154.9, 133.9, 130.2, 129.9 (x 2), 124.0 (x 2), 38.7, 38.6, 31.5, 20.4, 17.8, 15.1. HRMS
(ESI+): calcd for C13H18N4S [M+H]+ 263.1327, found 263.1325.

2.2.9 (S)-5-((2,3-Dimethylbutyl)sulfonyl)-1-phenyl-1H-tetrazole (23)
A mixture of sulphide 32 (1.24 g, 4.73 mmol), (NH4)6Mo7O244H2O (584 mg, 0.47 mmol),
H2O2 (30%, 2.84 mL, 25 mmol) and EtOH (24 mL) was stirred at ambient temperature for 48 h.
Then it was diluted with water (75 mL) and extracted with Et2O (4 x 20 mL). The combined
extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was
chromatographed on SiO2 (PE-EtOAc, 100:0  92:8) to give sulfone 23 (1.332 g, 96%) as viscous
colourless oil. [훼]퐷20 = 4.82 (c 0.250, CH2Cl2). 1H NMR (CDCl3): δ 7.71 – 7.63 (m, 2H), 7.66 –
7.55 (m, 3H), 3.84 (dd, J = 14.4, 3.7 Hz, 1H), 3.52 (dd, J = 14.4, 9.0 Hz, 1H), 2.27 (dddd, J = 13.6,
8.5, 7.0, 3.9 Hz, 1H), 1.84 (pd, J = 6.8, 4.2 Hz, 1H), 1.10 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.9 Hz,
2H), 0.90 (d, J = 6.8 Hz, 2H). 13C NMR (CDCl3): δ 154.2, 133.2, 131.6, 129.8 (x 2), 125.3 (x 2),
60.1, 33.3, 32.5, 19.4, 17.8, 15.8. HRMS (ESI+): calcd for C13H18N4NaO2S [M+Na]+ 317.1043,
found 317.1043.
2.2.10 (22Z,24S)-6β-Methoxy-24-methyl-3,5-cyclo-5-cholest-22-ene (34)
A freshly prepared solution of LiHMDS (prepared by addition of 0.91 M BuLi (0.66 mL, 0.60 mmol) to a
solution of HMDS (0.13 mL, 0.62 mmol) in THF (0.62 mL) was added dropwise under argon at -55 oC to a
solution of sulfone 23 (176 mg, 0.60 mmol) in THF (1.2 mL). After stirring the reaction mixture at this
temperature for 70 min, a solution of the aldehyde 33 (103 mg, 0.30 mmol, prepared according to [35,
o
36]) in THF (0.60 mL) was added. The mixture was stirred at -55 C for 1 h, then the cooling bath was
removed and the mixture was kept overnight at ambient temperature. Water (270 L) was added, and
after stirring for 1 h, the mixture was diluted with EtOAc (10 mL) and washed with water (10 mL). After
separating the organic layer, the aqueous layer was extracted with EtOAc (3  3 mL). The combined
organic layers were dried over Na2SO4 and evaporated. The residue was chromatographed on SiO2 (PE-
EtOAc, 98:2) to give olefin 34 (64 mg, 52%) as a colorless oil, containing about 4% of the corresponding
22E-isomer (measured by the ratio of signals at 5.06 (m, 1H, 22Z-isomer), 4.98 (t, 1H, 22Z-isomer) and
5.16 (m, 2H, 22E-isomer)). The product was crystallized from methanol to give white crystals with mp 86-

88 oC, containing about 1% of the 22E-isomer. [훼]퐷20 = 27.4 (c 0.543, CHCl3). NMR data are summarized in
Table 1. HRMS (APCI): calcd for C29H49O [M+H]+ 413.3778, found 413.3773.
2.2.11 (24R)-6β-Methoxy-24-methyl-3,5-cyclo-5-cholestane (35)
A mixture of olefin 34 (24.6 mg, 60 mol), PtO2 (12.3 mg, 50% w/w), EtOAc (700 L) and EtOH (1160
L) was hydrogenated under atmospheric pressure at room temperature until .the ·necessary quantity of
hydrogen was absorbed. After completion of the reaction, the mixture was filtered through a pad of Celite,
and the filtrate was concentrated under reduced pressure. Purification of the crude product by flash
20
chromatography on silica gel (PE-EtOAc, 98:2) afforded campestane 35 (21 mg, 82%) as an oil. [훼]퐷
=
48.3 (c 0.697, CHCl3). 1H NMR (CDCl3): δ 3.32 (s, 3H), 2.77 (t, J = 2.8 Hz, 1H), 1.99 (dt, J = 12.5, 3.2 Hz, 1H),
1.89 (dt, J = 13.4, 2.9 Hz, 1H), 1.02 (s, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.85 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 6.8
Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 1.8 Hz, 3H), 0.64 (dd, J = 5.0, 3.8 Hz, 1H), 0.43 (dd, J = 8.0, 5.0
Hz, 1H). 13C NMR (CDCl3): δ 82.6, 56.7 (x 2), 56.5, 48.2, 43.5, 42.9, 40.5, 39.0, 36.1, 35.5, 35.2, 33.8, 33.5,
32.6, 30.6, 30.5, 28.5, 25.1, 24.3, 22.9, 21.7, 20.4, 19.4, 18.8, 18.4, 15.5, 13.2, 12.4. HRMS (APCI): calcd for
C29H50O [M+H]+ 415.3934, found 415.3935.
2.2.12 (22Z,24S)-24-Methylcholesta-5,22-dien-3β-ol (36) /cis-22-dehydrocampesterol
(36)/
A mixture of 34 (25 mg, 61 mol), TsOH•H2O (2.7 mg, 14 mol), dioxane (2.7 mL) and water (0.9 mL)
was stirred at at 75 oC for 4 h. Then solvents were evaporated, the residue was dissolved in EtOAc (10 mL)
and washed with water (5 mL). The water layer was extracted with EtOAc (3  3 mL). The combined organic
phases were dried over Na2SO4, and evaporated. The residue was chromatographed on SiO2 (PE-EtOAc,
85:15  80:20) to give sterol 36 (21 mg, 87%) as white crystals. [훼]퐷20 = -60.7 (c 0.257, CHCl3). Mp 161-
163 oC (methanol). NMR data are summarized in Table 1. HRMS (APCI): calcd for C28H47O [M+H]+ 399.3621,
found 399.3598; calcd for C28H45 [M+H-H2O]+ 381.3516, found 381.3517.
Table 1 – 1H and 13C NMR spectroscopic data for compounds 34 and 36a,b,c
Position
Compound

ether 34
cis-22-dehydrocampesterol (36)
, H
, C
33.5
25.1
21.7
13.2
, H
, C
1
2
3
4
1.50 (m, 1H) / 0.86 (m, 1H)
1.74 (m, 1H) /1.52 (m, 1H)
0.88 (m, 1H)
37.4
31.8
71.9
42.45
1.85 (m, 1H) / 1.08 (m, 1H)
1.84 (m, 1H) / 1.52 (m, 1H)
3.52 tt (11.2, 4.7)
0.65 (t, J = 4.3 Hz, 1H) /0.43 (dd, J =
7.9, 5.1 Hz, 1H)
2.28 (m, 1H) / 2.23 (m, 1H)
5
6
7
35.4
82.6
35.2
-
140.9
121.8
32.0
-
2.77 (t, J = 2.5, 1H)
1.89 (dt, J = 13.5, 2.9 Hz, 1H) /1.05
(m, 1H)
5.35 (m, 1H)
1.97 (m, 1H)/1.53 (m, 1H)
8
30.7
48.3
42.8
22.9
40.4
1.71 (m, 1H)
32.1
50.3
36.7
21.2
39.9
1.44 (m, 1H)
0.93 (m, 1H)
9
0.81 (m, 1H)
10
11
12
1.41 (m, 2H)
1.51 (m, 1H) / 1.45 (m, 1H)
1.99 (m, 1H) / 1.19 (m, 1H)
1.97 (dt, J = 12.5, 3.2 Hz, 1H) / 1.16
(m, 1H)
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
OMe
43.5
56.8
24.3
28.6
56.3
12.7
19.5
34.7
20.7
131.3
135.5
38.4
33.5
20.1
20.5
18.8
56.7
-
42.38
57.0
24.4
28.5
56.1
12.3
19.6
34.6
20.7
131.3
135.4
38.5
33.5
20.1
20.5
18.8
-
1.04 (m, 1H)
1.01 (m, 1H)
1.56 (m, 1H) / 1.11 (m, 1H)
1.67 (m, 1H) / 1.13 (m, 1H)
1.13 (m, 1H)
1.54 (m, 1H) / 1.03 (m, 1H)
1.69 (m, 1H) / 1.14 (m, 1H)
1.12 (m, 1H)
0.75 (s, 3H)
0.72 (s, 3H)
1.03 (s, 3H)
1.01 (s, 3H)
2.39 (m, 1H)
2.39 (m, 1H)
0.95 (d, J = 6.5 Hz, 3H)
4.97 (t, J = 10.6 Hz, 1H)
5.06 (t, J = 10.5 Hz, 1H)
2.21 (m, 1H)
0.96 (d, J = 6.5 Hz, 3H)
4.98 (t, J = 10.6 Hz, 1H)
5.06 (t, J = 10.5 Hz, 1H)
2.20 (m, 1H)
1.39 (m, 1H)
1.40 (m, 1H)
0.83 (d, J = 6.7 Hz, 3H)
0.88 (d, J = 6.7 Hz, 3H)
0.91 (d, J = 6.7 Hz, 3H)
3.32 (s, 3H)
0.83 (d, J = 6.8 Hz, 3H)
0.87 (d, J = 6.7 Hz, 3H)
0.91 (d, J = 6.7 Hz, 3H)
a NMR chemical shifts () are from spectra obtained in CDCl3 solutions.
b Assigned by DEPT, COSY, HSQC, and HMBC experiments.
c J values (in Hz) in parentheses.

3
Results and Discussion
C23-C28 subunits 17-20, 23 are small bulky molecules bearing a stereocenter and a functional
group required for their further coupling with a steroidal core. Although the molecules are small,
their synthesis is a laborious task associated with necessity of large quantity of chiral chemicals
and volatility of the intermediates. Nitroalcohol 22 is a chiral compound easily accessible through
the reported by Gellman organocatalytic Michael addition of isovaleraldehyde to nitroethylene
[33] (Scheme 2). For its preparation, only 2% of easily available from natural L-proline catalyst
21 [37, 38] is necessary and we assumed that compound 22 might be a good starting point in
synthesis of the target subunit if we develop an efficient way of the nitromethyl group removal.
As far as this group can be easily transformed to an aldehyde or acid moiety, decarbonylation or
decarboxylation reactions can be used to form the required hydrocarbon backbone. At the
beginning, we tested decarbonylation strategy based on the rhodium-catalyzed reaction of
aldehydes reported by O’Connor [39]. Taking into account a significant increase in volatility of
the molecule after decarbonylation, the hydroxyl group in 22 was protected as a TBDPS ether. To
transform the nitromethyl group into the aldehyde, the silylated nitroalcohol was reacted with
potassium carbonate and potassium permanganate according to Steliou’s protocol [40]. Attempts
to prepare aldehyde 24 by either a sequence of the base-mediated nitronate formation followed by
its acid-catalyzed hydrolysis [41] or by the reaction with sodium peroxocarbonate [42] were
unsuccessful. The best result on decarbonylation of aldehyde 24 was achieved when the substrate
was heated at 100oC in toluene in the presence of 10% of Wilkinson’s catalyst and 1 equiv of
DPPA [39]. Delightfully, the yield of the reaction was higher than that in stoichiometric version
of the reaction (entries 1-2). Changing the solvent to THF, which was originally used by O’Connor
and coworkers [39], was detrimental for the reaction (entries 3-4). Decreasing of amount of the
catalyst to 5% resulted in significant decrease in the yield (entry 5). Attempts of decarbonylation
of 24 under palladium catalysis [43] were unsuccessful and resulted only in recovery of the starting
material or formation of complex mixtures. Although overall yield of 25 was good enough, the

necessity of using the expensive rhodium catalyst encouraged us to continue our search for an
alternative way of dehomologation of 22. One more disadvantage of the developed approach was
observed on the stage of desilylation of 25 by tetrabutylammonium fluoride (not shown).
Separation of the formed volatile alcohol from TBDPSF was impossible in our hands.
Ph
Ph
N
OTMS
H
21
2 mol %
1) TBDPSCl, ImH (68%)
2) KMnO4, K2CO3 (84%)
NO2
3-nitrobenzoic acid (20%), rt, 24 h,
toluene, then NaBH4, MeOH
NO2
+
RO
O
78%, >99% ee
Ref.33
16
22
R=H,
22a
R=TBDPS,
(Ph3P)3RhCl (10%), DPPA (1 equiv),
toluene, 100 oC
O
TBDPSO
TBDPSO
83%
25
24
24
Optimization of rhodium-catalyzed decarbonylation of
entry
deviations from above
yield
1
2
3
4
5
none
83%
100% of (Ph3P)3RhCl, without DPPA 72%
THF instead of toluene, rt
THF instead of toluene, 60 oC
5% of (Ph3P)3RhCl
0%
0%
54%
Scheme 2. Synthesis of the ether 25
Both of the disadvantages mentioned above were overcome when decarboxylation reaction was used
key step instead of decarbonylation. Precious-metal catalysis is not necessary for
as
a
hydrodecarboxylation, which can be performed under nickel catalysis [44] or in the presence of organic
photoredox catalyst under irradiation by visible light [45]. Moreover, nitromethyl group can be
transformed to acid moiety under acidic conditions [46] permitting protection of the hydroxyl group in 22
as an ester instead of silyl ether. At first, the hydroxyl group in nitroalcohol 22 was benzoylated and the
carboxylic acid unit was formed by the reaction of the protected 26 with sodium nitrite and acetic acid
(Scheme 3). Initially, we tried to decarboxylate unactivated acid 27 under photoredox catalysis [45] but
only recovery of the starting material was observed. The desired transformation was successfully
accomplished using the protocol recently reported by Baran [44]. Carboxylic acid 27 was transformed to

NHPI ester 28 that was engaged into the nickel-catalyzed decarboxylation. An acceptable 47% yield of 29
was achieved in the presence of 20% of bathophenanthroline (L1) as a ligand when the reaction was
carried out on a 2 mmol scale (entry 1). At a scale lowered to 0.1 mmol, the yield was only a little higher
(entry 2). In the presence of 4,4′-di-tert-butyl-2,2′-dipyridyl (L2) ligand, the reaction proceeded less
efficiently (entry 3). Amount of phenylsilane had a significant effect on the yield of the reaction, which
was greater in the presence of 3 eq of the source of hydrogen as compared to the experiment when only
1.5 eq were added (entries 2 and 4).
O
N OH
O
1) BzCl, Py (90%);
2) NaNO2, AcOH, DMSO (89%)
O
OH
NO2
DIC, DMAP, CH2Cl2
98%
BzO
RO
27
22
R=H,
26
R=Bz,
O
.
L1
NiCl2 6H2O (10%),
(20%), Zn (0.5 eq), PhSiH3 (3 eq),
N
THF- DMF- iPrOH, 45 oC, 1 h
O
BzO
O
O
47%
BzO
29
28
Ph
Ph
28
Optimization of decarboxylation of
L1
:
entry
deviations from above
yield
N
N
N
N
1
2
3
4
none (2 mmol scale)
none (0.1 mmol scale)
47%
54%
43%
33%
tBu
tBu
L2
L1
(0.1 mmol scale)
instead of
L2:
1.5 eq of PhSiH3 instead of 3 eq
(0.1 mmol scale)
Scheme 3. Ni-catalyzed decarboxylation of NHPI redox-active ester 28
With benzoate 29 in hands, we easily synthesized the target C23-C28 subunit 23 bearing
phenyltetrazolylsulfonyl moiety (Scheme 4). Saponification of 29 furnished the volatile alcohol 30, which,
without purification, was coupled with thiol 31 giving thioether 32 in a 95% yield over 2 steps. Finally,
oxidation of 32 afforded the required sulfone 23 in a 96% yield, which was further successfully employed
in construction of saturated and unsaturated campestane side chains. The Julia-Kocienski olefination [47,
48] of steroidal aldehyde 33 with lithiated sulfone 23 furnished an unusual for this reaction Z-isomer of
steroid 34 (Z:E = 25:1). Configuration of the alkenyl unit was confirmed by 2D NOESY NMR experiment

(see SI). The obtained alkene was rearranged to (Z)-22-dehydrocampesterol (36), which is a rare and
poorly studied component of biological membranes [49-54]. As far as campestane steroids bearing 22E-
alkenyl fragment are demanded as synthetic intermediates and naturally occurring as well, we tried to
alter the selectivity of the olefination. Typically, E-selectivity in the Julia-Kocienski reaction can be
increased by changing the base from LiHMDS to KHMDS [ref]. However, under the modified conditions,
we observed significant drop of the yield of 34 to 7% and only moderate selectivity of the reaction (Z:E
=45:55). The saturated campestane side chain is presented in such steroids as campesterol (1) and
swinhoeisterol A (5) and this unit can be easily formed by simple platinum-catalyzed hydrogenation of 34,
which proceeds smoothly giving steroid 35 in a 82% yield.
SH
N
N
N
N
Ph
31
(NH4)6MoO24, H2O2
96%
PPh3, DEAD
S
N
RO
N
N
N
95% over 2 steps
Ph
32
29
30
R=Bz,
R=H,
KOH
O
H
H
(S)
H
33
OMe
O O
S
H
LiHMDS, toluene
N
H
H
N
N
52%
N
Ph
23
34
p-TsOH,
OMe
87%
H2O-dioxane,
80 oC
H2, PtO2
82%
(S)
(R)
H
H
H
H
H
H
HO
OMe
35
36
Scheme 4. Synthesis of 23 and its application in construction of the campestane side chain
Conclusion
In conclusion, a catalytic way to C23-C28 subunit of 24α-methyl steroids has been developed. The
approach is based on dehomologation of (S)-2-isopropyl-4-nitrobutan-1-ol, which is easily available on

multigram scale via an asymmetric reaction catalyzed by only 2% of an organocatalyst. Removal of the
extra carbon atom from this molecule was efficiently performed through a sequence of nitromethyl to
carboxyl group transformation and nickel-catalyzed decarboxylation of the obtained acid after its
activation. The synthesized C23-C28 fragment bearing phenyltetrazolylsulfonyl group is suitable for its
coupling with a steroidal aldehyde by the Julia-Kocienski reaction and we have successfully constructed
side chains presented in such steroids as campestane, swinhoeisterol A and (Z)-22-dehydrocampesterol.
Acknowledgments
The financial support by the Belarusian Foundation for Fundamental Research (project X17PM-039)
and the Russian Foundation for Basic Research (Grant No. 17-53-04070) is greatly appreciated.

References
[1]
[2]
H. Schaller, The role of sterols in plant growth and development, Prog. Lipid Res. 42(3)
(2003) 163-175. https://doi.org/10.1016/S0163-7827(02)00047-4.
L.J. Goad, G.G. Holz, D.H. Beach, Identification of (24S)-24-methylcholesta-5,22-dien-
3β-ol as the major sterol of a marine cryptophyte and a marine prymnesiophyte,
Phytochemistry 22(2) (1983) 475-476. https://doi.org/10.1016/0031-9422(83)83028-3.
M.D. Grove, G.F. Spencer, W.K. Rohwedder, N. Mandava, J.F. Worley, J.D. Warthen,
G.L. Steffens, J.L. Flippen-Anderson, J.C. Cook, Brassinolide, a plant growth-promoting
steroid isolated from Brassica napus pollen, Nature 281(5728) (1979) 216-217.
https://doi.org/10.1038/281216a0.
[3]
[4]
[5]
V.A. Khripach, V.N. Zhabinskii, A. de Groot, Brassinosteroids. A New Class of Plant
Hormones, Academic Press, San Diego, 1999.
M.F. Feldlaufer, E.W. Herbert, J.A. Svoboda, M.J. Thompson, W.R. Lusby, Makisterone
A: The major ecdysteroid from the pupa of the honey bee, Apis mellifera, Insect
Biochemistry 15(5) (1985) 597-600. https://doi.org/10.1016/0020-1790(85)90120-9.
J. Gong, P. Sun, N. Jiang, R. Riccio, G. Lauro, G. Bifulco, T.-J. Li, W.H. Gerwick, W.
Zhang, New steroids with a rearranged skeleton as (h)P300 inhibitors from the sponge
Theonella swinhoei, Org. Lett. 16(8) (2014) 2224-2227.
[6]
https://doi.org/10.1021/ol5007345.
[7]
[8]
[9]
J. Li, H. Tang, T. Kurtán, A. Mándi, C.-L. Zhuang, L. Su, G.-L. Zheng, W. Zhang,
Swinhoeisterols from the South China Sea Sponge Theonella swinhoei, J. Nat. Prod.
81(7) (2018) 1645-1650. https://doi.org/10.1021/acs.jnatprod.8b00281.
M. Anastasia, P. Allevi, P. Ciuffreda, A. Fiecchi, Stereoselective synthesis of crinosterol
[(22E,24S)-ergosta-5,22-dien-3-ol], J. Chem. Soc., Perkin Trans. 1 (10) (1983) 2365-
2367. https://doi.org/10.1039/P19830002365.
S. Takatsuto, N. Ikekawa, Synthesis of [26,28-2H6]crinosterol, a synthetic intermediate of
[26,28-2H6]brassinolide and [26,28-2H6]castasterone, J. Chem. Soc., Perkin Trans. 1 (4)
(1986) 591-593. https://doi.org/10.1039/P19860000591.
[10] V.A. Khripach, V.N. Zhabinskii, O.V. Konstantinova, N.B. Khripach, A.P. Antonchick,
B. Schneider, [3,3]-Claisen rearrangements in 24-methyl steroid synthesis: Application
to campesterol, crinosterol, and 25-crinosterol side chain construction, Steroids 67(7)
(2002) 597-603. https://doi.org/10.1016/S0039-128X(02)00007-7.

[11] V.A. Khripach, V.N. Zhabinskii, Y.V. Ermolovich, O.V. Gulyakevich, Synthesis of [26-
2H3]-campesterin and [26-2H3]-campestanol, deuterated analogs of biosynthetic
precursors of 28C-brassinosteroids, Chem. Nat. Compd. 48(4) (2012) 606-609.
https://doi.org/10.1007/s10600-012-0323-0.
[12] A.L. Hurski, V.N. Zhabinskii, V.A. Khripach, A new approach to the side chain
formation of 24-alkyl-22-hydroxy steroids: application to the preparation of early
brassinolide biosynthetic precursors, Steroids 77(7) (2012) 780-790.
https://doi.org/10.1016/j.steroids.2012.03.010.
[13] V.A. Khripach, V.N. Zhabinskii, O.V. Konstantinova, A.P. Antonchick, B. Schneider,
Synthesis of [26-2H3]brassinosteroids, Steroids 67(7) (2002) 587-595.
https://doi.org/10.1016/S0039-128X(02)00004-1.
[14] V.A. Khripach, V.N. Zhabinskii, O.V. Konstantinova, N.B. Khripach, Ireland-Claisen
rearrangement of steroidal 23-22-alcohols: an application to 22,25-24-alkyl steroid
synthesis, Tetrahedron Lett. 41(30) (2000) 5765-5767. https://doi.org/10.1016/S0040-
4039(00)00900-X.
[15] V.A. Khripach, V.N. Zhabinskii, N.D. Pavlovskii, Synthesis of (22R,23R,24S)-24-
methyl-5-cholestane-3,6,22,23-tetraol, a biosynthetic precursor of brassinolide, Russ.
J. Org. Chem. 37(11) (2001) 1570-1574. https://doi.org/10.1023/A:1013804119279.
[16] K. Mori, M. Sakakibara, Y. Ichikawa, H. Ueda, K. Okada, T. Umemura, G. Yabuta, S.
Kuwahara, M. Kondo, M. Minobe, A. Sogabe, Synthesis of (22S,23S)-homobrassinolide
and brassinolide from stigmasterol, Tetrahedron 38(14) (1982) 2099-2109.
https://doi.org/10.1016/0040-4020(82)85157-0.
[17] T. Schmittberger, D. Uguen, A formal synthesis of brassinolide, Tetrahedron Lett. 38(16)
(1997) 2837-2840. https://doi.org/10.1016/S0040-4039(97)00474-7.
[18] V.A. Khripach, V.N. Zhabinskii, A.P. Antonchick, O.V. Konstantinova, B. Schneider,
Synthesis of hexadeuterated 23-dehydroxybrassinosteroids, Steroids 67(13-14) (2002)
1101-1108. https://doi.org/10.1016/S0039-128X(02)00071-5.
[19] V.A. Khripach, V.N. Zhabinskii, K.V. Parkhimovich, O.V. Gulyakevich, Synthesis of
brassinolide and its biosynthetic precursors using methyl-3-hydroxy-2-methylpropionate,
Russ. J. Bioorg. Chem. 35(2) (2009) 240-249.
https://doi.org/10.1134/S1068162009020137.
[20] A.P. Antonchick, B. Schneider, V.N. Zhabinskii, V.A. Khripach, Synthesis of [26,27-
2H6]brassinosteroids from 23,24-bisnorcholenic acid methyl ester, Steroids 69(10) (2004)
617-628. https://doi.org/10.1016/j.steroids.2004.05.014.

[21] N.M. O’Connell, Y.C. O’Callaghan, N.M. O’Brien, A.R. Maguire, F.O. McCarthy,
Synthetic routes to campesterol and dihydrobrassicasterol: a first reported synthesis of the
key phytosterol dihydrobrassicasterol, Tetrahedron 68 (2012) 4995-5004.
https://doi.org/10.1016/j.tet.2012.04.060.
[22] P. Ferraboschi, E. Santaniel, A convenient synthesis of (S)-2-methyl and (2S)-2,3-
dimethyl butyl phenylsulfones from (S)-(-)-3-methyl-γ-butyrolactone, Synth. Commun.
14(13) (1984) 1199-1204. https://doi.org/10.1080/00397918408076800.
[23] R. Kiesgen de Richter, M. Bonato, M. Follet, J.M. Kamenka, The (+)- and (-)-[2-(1,3-
dithianyl)]myrtanylborane. Solid and stable monoalkylboranes for asymmetric
hydroboration, J. Org. Chem. 55(9) (1990) 2855-2860.
https://doi.org/10.1021/jo00296a054.
[24] M. Sato, N. Miyaura, A. Suzuki, Rhodium(I)-catalyzed asymmetric hydroboration of
alkenes with 1,3,2-benzodioxaborole, Tetrahedron Lett. 31(2) (1990) 231-234.
https://doi.org/10.1016/S0040-4039(00)94379-X.
[25] A.Z. Gonzalez, J.G. Roman, E. Gonzalez, J. Martinez, J.R. Medina, K. Matos, J.A.
Soderquist, 9-Borabicyclo[3.3.2]decanes and the asymmetric hydroboration of 1,1-
disubstituted alkenes, J. Am. Chem. Soc. 130(29) (2008) 9218-9219.
https://doi.org/10.1021/ja803119p.
[26] H.C. Brown, R.G. Naik, R.K. Bakshi, C. Pyun, B. Singaram, Synthetic utility of boronic
esters of essentially 100% optical purity. Synthesis of homologated boronic acids and
esters of very high enantiomeric purities, J. Org. Chem. 50(26) (1985) 5586-5592.
https://doi.org/10.1021/jo00350a031.
[27] T. Uemura, X. Zhang, K. Matsumura, N. Sayo, H. Kumobayashi, T. Ohta, K. Nozaki, H.
Takaya, Highly efficient enantioselective synthesis of optically active carboxylic acids by
Ru(OCOCH3)2[(S)-H8-BINAP], J. Org. Chem. 61(16) (1996) 5510-5516.
https://doi.org/10.1021/jo960426p.
[28] G. Filippini, M. Silvi, P. Melchiorre, Enantioselective formal α-methylation and α-
benzylation of aldehydes by means of photo-organocatalysis, Angew. Chem., Int. Ed.
56(16) (2017) 4447-4451. https://doi.org/10.1002/anie.201612045.
[29] L.F. Tietze, C. Raith, C.C. Brazel, S. Hölsken, J. Magull, Enantioselective synthesis of 2-
substituted alcohols using (+)-(1S,2S)-pseudoephedrine as chiral auxiliary, Synthesis
2008(02) (2008) 229-236. https://doi.org/10.1055/s-2008-1000851.
[30] K.-C. Cheng, B. Luu, G. Ourisson, J.P. Beck, Chemistry and biochemistry of Chinese
drugs. Part IV. Stereoselective partial synthesis and cytotoxicity of 7- and 22-

hydroxylated derivatives of 24-methylcholesterols, J. Chem. Res., Synop. (3) (1979) 84-
85.
[31] J. Hang, P. Dussault, A concise synthesis of β-sitosterol and other phytosterols, Steroids
75(12) (2010) 879-883. https://doi.org/10.1016/j.steroids.2010.05.016.
[32] A. Hurski, V. Zhabinskii, V. Khripach, A short convergent synthesis of the side chains of
brassinolide, cathasterone, and cryptolide, Tetrahedron Lett. 54(6) (2013) 584-586.
https://doi.org/10.1016/j.tetlet.2012.11.094.
[33] Y. Chi, L. Guo, N.A. Kopf, S.H. Gellman, Enantioselective organocatalytic Michael
addition of aldehydes to nitroethylene: efficient access to γ2-amino acids, J. Am. Chem.
Soc. 130(17) (2008) 5608-5609. https://doi.org/10.1021/ja800345r.
[34] W.L.E. Armarego, Purification of Laboratory Chemicals, 8th ed., Butterworth-
Heinemann, Amsterdam, 2017.
[35] J.A. Steele, E. Mosettig, The solvolysis of stigmasteryl tosylate, J. Org. Chem. 28(2)
(1963) 571-572. https://doi.org/10.1021/jo01037a505.
[36] J.J. Pappas, W.P. Keaveney, E. Gancher, M. Berger, A new and convenient method for
converting olefins to aldehydes, Tetrahedron Lett. 7(36) (1966) 4273-4278.
https://doi.org/10.1016/S0040-4039(00)76049-7.
[37] K.L. Jensen, G. Dickmeiss, H. Jiang, Ł. Albrecht, K.A. Jørgensen, The diarylprolinol
silyl ether system: a general organocatalyst, Acc. Chem. Res. 45(2) (2012) 248-264.
https://doi.org/10.1021/ar200149w.
[38] Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji, Diphenylprolinol silyl ethers as efficient
organocatalysts for the asymmetric Michael reaction of aldehydes and nitroalkenes,
Angew. Chem., Int. Ed. 44(27) (2005) 4212-4215.
https://doi.org/doi:10.1002/anie.200500599.
[39] J.M. O'Connor, J. Ma, Metal-catalyzed decarbonylation of primary aldehydes at room
temperature, J. Org. Chem. 57(19) (1992) 5075-5077.
https://doi.org/10.1021/jo00045a015.
[40] K. Steliou, M.A. Poupart, Synthesis of aldehydes and ketones from nitro paraffins, J.
Org. Chem. 50(24) (1985) 4971-4973. https://doi.org/10.1021/jo00224a067.
[41] H. Chikashita, Y. Morita, K. Itoh, Transformation of aromatic nitroalkanes into carbonyl
compounds by the improved Nef reaction, Synth. Commun. 17(6) (1987) 677-683.
https://doi.org/10.1080/00397918708075741.
[42] C. Narayana, N.K. Reddy, G.W. Kabalka, Sodium percarbonate: a mild reagent for
conversion of tosylhydrazones and nitroalkanes to carbonyl compounds, Synth.
Commun. 22(17) (1992) 2587-2592. https://doi.org/10.1080/00397919208021655.

[43] A. Modak, A. Deb, T. Patra, S. Rana, S. Maity, D. Maiti, A general and efficient
aldehyde decarbonylation reaction by using a palladium catalyst, Chemical
Communications 48(35) (2012) 4253-4255. https://doi.org/10.1039/C2CC31144E.
[44] T. Qin, L.R. Malins, J.T. Edwards, R.R. Merchant, A.J. Novak, J.Z. Zhong, R.B. Mills,
M. Yan, C. Yuan, M.D. Eastgate, P.S. Baran, Nickel-catalyzed Barton decarboxylation
and Giese reactions: a practical take on classic transforms, Angew. Chem., Int. Ed. 56(1)
(2017) 260-265. https://doi.org/10.1002/anie.201609662.
[45] J.D. Griffin, M.A. Zeller, D.A. Nicewicz, Hydrodecarboxylation of carboxylic and
malonic acid derivatives via organic photoredox catalysis: substrate scope and
mechanistic insight, J. Am. Chem. Soc. 137(35) (2015) 11340-11348.
https://doi.org/10.1021/jacs.5b07770.
[46] C. Matt, A. Wagner, C. Mioskowski, Novel transformation of primary nitroalkanes and
primary alkyl bromides to the corresponding carboxylic acids, J. Org. Chem. 62(2)
(1997) 234-235. https://doi.org/10.1021/jo962110n.
[47] P.R. Blakemore, The modified Julia olefination: alkene synthesis via the condensation of
metallated heteroarylalkylsulfones with carbonyl compounds, J. Chem. Soc., Perkin
Trans. 1 (23) (2002) 2563-2585. https://doi.org/10.1039/B208078H.
[48] P.R. Blakemore, W.J. Cole, P.J. Kocieński, A. Morley, A stereoselective synthesis of
trans-1,2-disubstituted alkenes based on the condensation of aldehydes with metallated 1-
phenyl-1H-tetrazol-5-yl sulfones, Synlett 29(1) (1998) 26-28. https://doi.org/10.1055/s-
1998-1570.
[49] S. De Rosa, A. Milone, S. Popov, S. Andreev, Sterol composition of the Black Sea
Hydrozoan, Obelia longissima (Pallas 1766), Comp. Biochem. Physiol. Part B: Biochem.
Mol. Biol. 123(2) (1999) 229-233. https://doi.org/10.1016/S0305-0491(99)00065-6.
[50] K. Slantchev, K. Stefanov, K. Seizova, S. Popov, S. Andreev, Chemical Composition of
the Lipophylic Extract from the Tunicate Botryllus schlosseri, Zeitschrift für
Naturforschung C 55(9-10) (2000) 794-798. https://doi.org/10.1515/znc-2000-9-1020.
[51] K. Slantchev, F. Yalçın, T. Ersöz, J. Nechev, İ. Çalış, K. Stefanov, S. Popov,
Composition of Lipophylic Extracts from Two Tunicates, Styela sp. and Phallusia sp.
from the Eastern Mediterranean, Zeitschrift für Naturforschung C 57(5-6) (2002) 534-
540. https://doi.org/10.1515/znc-2002-5-623.
[52] S. De Rosa, Z. Kamenarska, V. Bankova, K. Stefanov, S. Dimitrova-Konaklieva, H.
Najdenski, I. Tzevtkova, S. Popov, Chemical composition and biological activities of the
Black Sea algae Polysiphonia denudata (Dillw.) Kutz. and Polysiphonia denudata f.

fragilis (Sperk) Woronich, Zeitschrift für Naturforschung C 56(11-12) (2001) 1008-1014.
https://doi.org/10.1515/znc-2001-11-1218.
[53] T. Akihisa, T. Tamura, T. Matsumoto, W.C.M.C. Kokke, P. Ghosh, S. Thakur,
(22Z,24S)-Stigmasta-5,22,25-trien-3β-ol and other novel sterols from Clerodendrum
scandens: first report of the isolation of a cis-Δ22-unsaturated sterol from a higher plant, J.
Chem. Soc., Perkin Trans. 1 (8) (1990) 2213-2218.
https://doi.org/10.1039/P19900002213.
[54] S.-I. Teshima, A. Kanazawa, T. Ando, A new C28-sterol: Isolation of 22-cis-24-Ξ-
methylcholesta-5,22-dien-3β-ol, Comparative Biochemistry and Physiology Part B:
Comparative Biochemistry 47(2) (1974) 507-514.
https://doi.org/https://doi.org/10.1016/0305-0491(74)90081-9.

Legends
Fig. 1. Structures of some natural steroids with a campestane side chain
Scheme 1. Approaches to the synthesis of campestane side chains 9,10 and C23-C28 fragments
17-20, 23
Scheme 2. Synthesis of the ether 25
Scheme 3. Ni-catalyzed decarboxylation of NHPI redox-active ester 28
Scheme 4. Synthesis of 23 and its application in construction of the campestane side chain
Table 1 – 1H and 13C NMR spectroscopic data for compounds 32 and 33a,b,c

Contacts
Viktoryia S. Yakimchyk, yakimchik.victoria@gmail.com, https://orcid.org/0000-0001-5657-
5346
Volha V. Kazlova, okozlova.94@gmail.com, https://orcid.org/0000-0003-2039-9509
Alaksiej L. Hurski, ahurski@iboch.by, https://orcid.org/0000-0002-8599-2621
Rimma G. Savchenko, rimasavchenko@mail.ru, https://orcid.org/0000-0001-9145-2253
Svetlana A. Kostyleva, skostyleva_89@mail.ru, https://orcid.org/0000-0002-9524-9460
Vladimir Zhabinskii, vz@iboch.by, https://orcid.org/0000-0001-8591-2794
Vladimir Khripach, khripach@iboch.by, https://orcid.org/0000-0002-3850-9860

catalytic
decarbonylative or
decarboxylative dehomologation
O O
S
NO2
N
HO
N
N
N
Ph
H
available via an asymmetric reaction
catalyzed by 2% of chiral catalyst
construction of side
campestanes
chains of


A new catalytic way to C23-C28 fragment of campestanes is reported
The synthesis is based on organocatalytic formation of the stereocenter followed by
dehomologation of the obtained synthetic intermediate

The synthesized subunit can be attached to a steroidal core by Julia-Kocienski olefination