Application of hypoiodite-mediated aminyl radical cyclization to synthesis of solasodine acetate

Article abstract of DOI:10.1016/j.steroids.2012.05.002

Solasodine acetate, an anticancer steroidal alkaloid, was synthesized from diosgenin in 8 steps with an overall yield of 23%. A key synthetic step involves the formation of 5/6-oxazaspiroketal moiety via hypoiodite-mediated aminyl radical cyclization of a steroidal primary amine.

Full text of DOI:10.1016/j.steroids.2012.05.002

Steroids 77 (2012) 1069–1074
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Steroids
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Application of hypoiodite-mediated aminyl radical cyclization to synthesis
of solasodine acetate
⇑
Yi Kou, Myong Chul Koag, Young Cheun, Aram Shin, Seongmin Lee
The Division of Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Solasodine acetate, an anticancer steroidal alkaloid, was synthesized from diosgenin in 8 steps with an
overall yield of 23%. A key synthetic step involves the formation of 5/6-oxazaspiroketal moiety via
hypoiodite-mediated aminyl radical cyclization of a steroidal primary amine.
Ó 2012 Elsevier Inc. All rights reserved.
Received 5 March 2012
Received in revised form 23 April 2012
Accepted 1 May 2012
Available online 11 May 2012
Keywords:
Hypoiodite
Solasodine acetate
Aminyl radical cyclization
Steroidal alkaloid
Oxazaspiroketal
1. Introduction
phosphoryl groups [16]) on the amino group that were typically
employed in other aminyl radical cyclization methods, we
Solasodine 1 [1], solasodine acetate 2 [2], and solarmargine
3 [3] are plant-derived steroidal alkaloids that share a 5/6-
oxazaspiroketal moiety (Fig. 1) and exhibit various biological activ-
ities. Solasodine has shown antiproliferative [4], neurogenesis [5],
anti-inflammatory [6], and anticonvulsant activities [7]. Solasodine
acetate 2 is known to damage DNA significantly and to increase
DNA repair activity [8]. DNA damage activities of solasodine
acetate 2 may be ascribed to its oxazaspiroketal moiety that can
produce a hypothetical imminium ion 4 (Fig. 1) [8]. Solamargine
3, a solasodine glycoalkaloid, is highly effective at treating skin
cancers [9], induces apoptosis [10], and is known to sensitize
breast cancer cells to cisplatin treatment [11].
expected that the radical-stabilizing group-free method would be
a valuable means for efficient preparation of various oxazaspirokt-
eal-containing natural products. Indeed, we have successfully
applied the methodology in the synthesis of an analog of cepha-
lostatin 11 [16], a bis-steroidal pyrazine anticancer agent [15].
We envisaged that solasodine acetate 2 also can be readily synthe-
sized from diosgenin 5 via ‘‘Reduction/Oxidation’’ modifications
and the hypoiodite-mediated aminyl radical cyclization (Scheme 1).
Herein, we report a facile synthesis of solasodine acetate 2, where
hypoiodite-mediated cyclization of a nonactivated primary amine
is used as a key chemical transformation.
Significant biological activities of the steroidal alkaloids
have prompted several research groups to undertake syntheses of
solasodine-related natural products (Fig. 2). Some of these synthe-
ses involve the use of key intermediates of steroidal diketone 6
[12], hemiacetal 7 [13], and cyclic enol ether 8 [14]. In conjunction
with our ongoing efforts to develop potent steroidal anticancer
agents, we recently discovered that hypoiodite-mediated radical
cyclization of a primary amine 9 proceeded smoothly at 0 °C to
give an oxazaspiroketal 10 in the presence of iodobenzene diace-
tate and iodine (Fig. 3) [15]. Since our cyclization conditions do
not require a radical-stabilizing groups (e.g. acetyl, sulfonyl, and
2. Experimental
2.1. General Methods
Reagents, such as triethylsilane, boron trifluoride etherate,
iodine, iodobenzene diacetate, triphenylphosphine, sodium azide,
and p-toluenesulfonyl chloride were purchased from Aldrich
Chemical Company Inc., were used as received. Acetonitrile, meth-
ylene chloride, pyridine, and triethylamine (TEA) were distilled
from calcium hydride: methanol was distilled from magnesium
turnings: THF was distilled from Na/benzoquinone. Sodium sulfate
(Na2SO4) was anhydrous. All chromatographic and workup sol-
vents were distilled.
⇑
Unless otherwise indicated, all reactions were carried out under
a positive pressure of argon in anhydrous solvents and the reaction
Corresponding author. Tel.: +1 512 471 1785; fax: +1 512 471 4726.
E-mail address: SeongminLee@mail.utexas.edu (S. Lee).
0039-128X/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.steroids.2012.05.002

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Y. Kou et al. / Steroids 77 (2012) 1069–1074
Fig. 1. Steroidal alkaloids: Solasodine 1, solasodine acetate 2 solamargine 3 and a hypothetical imminium ion 4.
Fig. 2. Previous syntheses of natural products containing solasodine moiety.
Fig. 3. Previous synthesis of oxazaspiroketal-containing cephalostatin analog 11 using a hypoiodite-mediated aminyl radical cyclization as a key reaction.
flasks were fitted with rubber septa for the introduction of
substrates and reagents via syringe. Progress of reactions was
monitored by thin layer chromatography (TLC) in comparison with
the starting materials. All TLC analyses were carried out on Merck
Silica Gel 60 F254 TLC plates, thickness of 0.25 mm. The plates
were visualized by ultraviolet illumination at 254 nm and immer-
sion in visualizing solution. The two commonly employed TLC
visualizing solutions were: (i) p-anisaldehyde solution (1350 mL
of absolute ethanol, 50 mL of concentrated H2SO4, 37 mL of p-
anisaldehyde), and (ii) permanganate solution (weight percents
of 1% KMnO4 and 2% Na2CO3 in water).
Analytical samples were obtained from flash silica gel chroma-
tography, using about 100 grams of silica gel of 230–400 mesh size
for purifying a gram of reaction mixture. 1H NMR and 13C NMR spec-
tra were recorded on a Bruker AM 500 (500 MHz). NMR spectra
were determined in chloroform-d (CDCl3) and are reported in parts
per million (ppm) from the residual chloroform (7.24 ppm and
77.0 ppm) and benzene (7.16 ppm and 128.39 ppm) standard,
respectively. Peak multiplicates in 1H-NMR spectra, when reported,
are abbreviated as s (singlet), d (doublet), t (triplet), m (multiplet),
and/or ap (apparent) and/or br (broad). Mass spectra were all ob-
tained on either a JEOL AX-505 or a JEOL SX-102.

Y. Kou et al. / Steroids 77 (2012) 1069–1074
1071
Scheme 1. Plan for solasodine acetate synthesis.
2.2. Chemical synthesis
(60 mg, 0.13 mmol) as an off-white solid (mp, 100–103 °C) in
64% yield.
2.2.1. (20
14
a
,22b,25R)-3b-Acetoxyfurost-5-ene-26-(p-toluenesulfonate)
1H NMR (300 MHz, CDCl3) d 5.36 (1H, m), 4.53 (1H, m), 4.26 (1H,
m), 3.28 (1H, m), 2.60 (1H, dd, J = 5.4, 12.6 Hz), 2.48 (1H, dd, J = 5.9,
12.5 Hz), 2.28 (2H, d, J = 7.2 Hz), 1.99 (3H, s), 1.00 (3H, s), 0.96 (3H,
d, J = 6.7 Hz), 0.87 (3H, d, J = 6. 7 Hz), 0.77 (3H, s); 13C NMR
(75 MHz, CDCl3) 170.5, 139.6, 122.4, 90.2, 83.1, 73.9, 65.1, 56.8,
50.0, 48.1, 40.6, 39.3, 38.0, 37.8, 36.9, 36.6, 36.2, 32.2, 31.9, 31.5,
31.1, 30.8, 27.7, 24.1, 21.4, 20.6, 19.2, 18.9, 17.2, 16.4.
HRMS for C29H48NO3 (M+H), calcd: 458.3628, found: 458.4634.
To a CH2Cl2 (50 mL) solution of diosgenin acetate 12 (4.03 g,
8.83 mmol) and triethylsilane (2.86 mL, 17.6 mmoL) was added
dropwise boron trifluoride diethyl etherate (2.50 g, 17.6 mmoL)
in CH2Cl2 (20 mL) at 0 °C. After stirring the resulting mixture for
12 h at an ambient temperature, the reaction was quenched by
slow addition of aqueous saturated sodium bicarbonate (200 mL).
Extraction of aqueous layer with CH2Cl2 (3 Â 200 mL), washing
with brine, drying over anhydrous sodium sulfate, and concentra-
tion under reduced pressure gave a crude primary alcohol 13,
which was subjected to the next reaction without further purifica-
tion. To a CH2Cl2 (70 mL) solution of alcohol 13 were added trieth-
ylamine (3.68 mL, 26.5 mmol), 4-dimethylaminopyridine (107 mg,
0.88 mmol), and p-toluenesulfonyl chloride (2.50 g, 13.2 mmol),
and the resulting mixture was vigorously stirred at 25 °C. After
6 h, the reaction mixture was concentrated under reduced pres-
sure, and subjected to silica gel chromatography (Hexane/
EtOAc = 8:1) to give tosylate 14 (4.62 g, 7.75 mmol) as a white solid
(mp, 116–119 °C) in 85% yield. 1H and 13C NMR chemical shifts val-
ues of compound 2 were consistent with the previously reported
values [17].
2.2.4. (20a,22b,25R)-3b-Acetoxy-5,6-epoxy-26-azidofurostane 17
To a stirred solution of trisubstituted alkene 15 (313 mg,
0.65 mmol) and NaHCO3 (273 mg, 3.25 mol) in 10 mL of CH2Cl2
was added portionwise m-chloroperoxybenzoic acid (319 mg,
1.30 mmol) over 10 min at 0 °C. After vigorously stirring the mix-
ture for 3 h at the same temperature, the reaction was quenched
by adding saturated sodium thiosulfate (10 mL). The reaction mix-
ture was extracted with ethyl acetate (3 Â 30 mL), washed with
brine, dried over anhydrous sodium sulfate, concentrated in vacuo,
and subjected to silica gel chromatography (Hexane/EtOAc = 4:1)
to give an inseparable mixture of diasteromeric epoxide 17
(280 mg, a:b = 2:1 based on 1H NMR integration of C3–H) as a col-
orless foam in 87% yield.
1H NMR (300 MHz, CDCl3) d 4.92 (0.66H, m, C3–H of the
a epox-
ide), 4.66 (0.33H, m, C3-H of the b epoxide), 3.21 (1H, m), 3.15 (1H,
d, J = 5.9 Hz), 3.03 (2H, m), 2.82 (1H, d, J = 4.1 Hz), 1.93 (3H, s), 1.02
(3H, d, J = 6.7 Hz), 0.92 (3H, d, J = 7.7 Hz), 0.67 (3H, s); 13C NMR
(75 MHz, CDCl3) 170.3, 170.0, 89.8, 82.8, 71.1, 64.9, 64.7, 63.1,
62.2, 58.8, 57.5, 56.9, 56.2, 50.8, 42.2, 40.5, 39.3, 38.8, 37.8, 37.7,
36.5, 36.0, 35.0, 34.9, 33.5, 32.4, 32.0, 31.9, 31.0, 30.5, 29.4, 39.3,
28.7, 27.0, 21.4, 21.2, 20.1, 18.8, 17.4, 17.0, 16.2, 16.1, 15.7. HRMS
for C29H46N3O4, (M+H), calcd: 500.3483, found: 500.3481.
2.2.2. (20a,22b,25R)-3b-Acetoxy-5-ene-26-azidofurostane 15
To a DMF (6 mL) solution of tosylate 14 (660 mg, 1.07 mmol)
was added sodium azide (208 mg, 3.20 mmol) and the mixture
was stirred for 3 h at 60 °C. The reaction mixture was then parti-
tioned between water (50 mL) and ethyl acetate (50 mL). The
aqueous layer was extracted with ethyl acetate (3 Â 20 mL), and
the combined organic extracts were washed with saturated
lithium chloride (50 mL). After removal of the organic solvents
under reduced pressure, the residue was subjected to silica gel
chromatography (Hexane/EtOAc = 8:1) to give azide 15 (350 mg,
0.72 mmol) as an off-white solid (mp, 60–63 °C) in 67% yield.
1H NMR (300 MHz, CDCl3) d 5.34 (1H, d, J = 3 Hz), 4.56 (1H, m),
4.27 (1H, m), 3.28 (1H, m), 3.22–3.06 (2H, m), 2.30 (3H, s), 1.00 (3H,
s), 0.97 (3H, d, J = 3.9 Hz), 0.93 (3H, d, J = 4.2 Hz), 0.78 (3H, s); 13C
NMR (75 MHz, CDCl3) 170.5, 139.7, 122.3, 90.0, 83.2, 73.8, 65.1,
57.7, 56.9, 50.0, 40.6, 39.4, 38.0, 37.9, 37.0, 36.7, 33.7, 32.2, 31.9,
31.5, 31.1, 30.7, 29.7, 27.7, 21.4, 20.6, 19.3, 18.9, 17.6, 16.4. HRMS
for C29H46N3O3 (M+H), calcd: 484.3534, found: 484.3530.
2.2.5. (20a,22b,25R)-3b-Acetoxy-26-amino-5,6-epoxy-furostane 18
To azide 17 (260 mg, 0.54 mmol) in THF/H2O (10 mL/0.2 mL)
was added triphenylphosphine (757 mg, 2.9 mmol), and the result-
ing mixture was stirred at 25 °C for 24 h. The reaction mixture was
concentrated under reduced pressure, and subjected to silica gel
chromatography (EtOAc/MeOH/TEA = 10:1:0.05) to provide a pri-
mary amine 18 (230 mg, 0.49 mmol) as a colorless foam in 87%
yield.
1H NMR (300 MHz, CDCl3) d 4.85–4.58 (1H, m), 4.14 (1H, m),
3.16 (1H, m), 2.94–2.75 (1H, m), 2.41 (2H, m), 1.87(3H, s), 0.96
(3H, s), 0.84 (3H, d, J = 6.7 Hz), 0.76 (3H, d, J = 6.4 Hz), 0.61(1H,
s); 13C NMR (75 MHz, CDCl3) 170.1, 170.0, 90.0, 82.7, 71.0, 64.8,
64.6, 63.1, 62.1, 58.7, 56.7, 56.0, 50.7, 48.0, 42.1, 40.4, 40.3, 39.2,
38.7, 37.6, 36.4, 36.1, 35.8, 34.9, 34.8, 32.3, 31.9, 30.8, 30.5, 29.3,
29.1, 28.6, 26.9, 21.2, 21.0, 19.9, 18.7, 17.0, 16.8, 16.1, 16.0, 15.6.
HRMS for C29H48NO4 (M + H), calcd: 474.3578, found: 474.3585.
2.2.3. (20a,22b,25R)-3b-Acetoxy-5-ene-26-aminofurostane 16
To a MeOH (10 mL) solution of (20
a,22b,25R)-3b-acetoxy-
5-ene-26-azidofurostane 15 (100 mg, 0.21 mmol) was added
triphenylphosphine (550 mg, 2.1 mmol) at an ambient tempera-
ture. The mixture was heated and stirred for 15 h at 60 °C. The pre-
cipitates were filtered through sintered glass, the filtrates were
concentrated under reduced pressure, and the residue was
subjected to silica gel chromatography (EA/MeOH/TEA = 1:1:0.02)
2.2.6. 5,6-epoxy-solasodine-3b-acteate 19
Iodobenzene diacetate (232 mg, 0.72 mmol) and I2 (181 mg,
0.72 mmol) were dissolved in CH2Cl2 (3 mL) by vigorous stirring
to give (20a,22b,25R)-3b-acetoxy-5-ene-26-aminofurostane 16

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Y. Kou et al. / Steroids 77 (2012) 1069–1074
for 30 min at room temperature. The mixture was then cooled
down to 0 °C and a CH2Cl2 solution (3 mL) of primary amine 18
(170 mg, 0.36 mmol) was added. After stirring for 2 h at 0 °C, the
reaction was quenched by adding saturated sodium thiosulfate
(20 mL), and the reaction mixture was extracted with CH2Cl2
(3 Â 20 mL) and dried over anhydrous Na2SO4. Concentration and
purification by silica gel chromatography (Hexane/EtOAc = 1:1)
gave an oxazaspiroketal 19 (100 mg, 0.21 mmol) as an off-white
solid (mp, 175–178 °C) in 77% yield.
alcohol 13 was converted into the corresponding azide 15 via
sequential tosylation of the alcohol 13 and nucleophilic substitu-
tion of the tosylate group with azide (Scheme 2). Staudinger
reduction [19] of alkyl azide 15 yielded a primary amine 16, which
set the stage for a crucial aminyl radical cyclization. Unfortunately,
when the steroidal amine 16 was treated with iodobenzene diace-
tate and iodine, the reaction gave a complex mixture of products
with no indication of formation of solasodine acetate 2. Proton
and carbon NMR spectra indicate that D5 olefin moiety was
affected under the influence of iodobenzene diaceate and iodine
[20], and this led us to seek a revised synthetic plan involving pro-
tection of
mediated cyclization (Scheme 3).
Our revised synthesis of solasodine acetate 2 began with an oxi-
dation of a trisubstituted alkene 15 with m-chloroperoxybenzoic
acid [21] to give a diasteromeric mixture (a:b = 2:1) of 5,6-epox-
ides 17 in 87% yield (Scheme 3). The resulting oxirane-azide 17
was then subjected to Staudinger reduction [19] to afford primary
amine 18. Gratifyingly, when the olefin moiety was protected with
an oxirane group, the hypoiodite-mediated intramolecular radical
cyclization [15] occurred smoothly at 0 °C to stereoselectivley fur-
nish 5/6 oxazaspiroketal 19 in 77% yield. Deoxygenation of oxirane
group in 19 with triphenylphosphine and iodine [22] smoothly
provided the target solasodine acetate 2 in 73% yield.
A potential mechanism for the formation of 5/6 oxazaspiroketal
19 via hypoiodite-mediated aminyl radical cyclization of 18 is
shown in Scheme 4. The action of PhI(OAc)2 and I2 on the primary
amine 18 produces N-iodoamine 20, which generates an aminyl
radical 21 and an iodine radical via a homolytic cleavage of the
N–I bond. Transposition of the aminyl radical 21 via 1,6-hydrogen
atom transfer gives a carbon radical 22, which is stabilized by the
adjacent oxygen atom in the THF ring. The carbon radical reacts
with iodine radical to give iodocyclic ether 23, which undergoes
oxygen atom-assisted removal of iodine to generate oxacarbenium
ion 24. The oxacarbenium ion is then quenched by the neighboring
primary amine to produce 5/6 oxazaspiroketal 19 stereoselectively.
In summary, we have developed an efficient synthetic route for
solasodine acetate 2, where hypoiodite-mediated cyclization of a
1H NMR (300 MHz, CDCl3) d 4.96 (1H, m), 4.74 (1H, m), 3.06–
2.63 (2H, m), 2.86 (1H, m), 1.98 (3H, s), 1.06 (3H, s), 0.98 (3H, s),
0.87 (3H, d, J = 6.4 Hz), 0.72 (3H, d, J = 7.2 Hz); 13C NMR (75 MHz,
CDCl3) 170.4, 170.1, 99.8, 99.7, 83.9, 77.4, 71.2, 65.1, 64.9, 63.2,
62.4, 61.1, 58.7, 56.0, 55.3, 50.6, 45.5, 42.0, 41.9, 40.9, 40.8, 38.5,
37.8, 35.9, 35.0, 34.6, 33.2, 32.0, 31.8, 31.5, 29.5, 29.3, 28.7, 27.8,
27.1, 25.2, 22.6, 21.3, 20.1, 18.5, 17.0, 16.6, 16.0, 15.8, 14.0. HRMS
for C29H46NO4 (M+H), calcd: 472.3421, found: 472.3423.
D
5 olefin moiety with oxirane group prior to hypoiodite-
2.2.7. Solasodine-3b-acetate 2
To a CH2Cl2 (2 mL) solution of epoxide 19 (25 mg, 0.055 mmol)
was added triphenylphosphine (39 mg, 0.15 mmol) and iodine
(38 mg, 0.15 mmol) and the mixture was stirred for 1 h at 25 °C.
The reaction mixture was quenched by adding saturated sodium
thiosulfate (5 mL), extracted with CH2Cl2 (3 Â 5 mL) and dried over
anhydrous sodium sulfate. Concentration and purification by silica
gel chromatography (Hexane/EtOAc = 1:1) afforded the target
solasodine acetate 2 (16 mg, 0.04 mmol) as a white solid (mp,
190–194 °C [lit mp 189–190 °C ref [14]]) in 73% yield. 1H and 13C
NMR chemical shifts values of compound 2 were consistent with
the previously reported values [14].
3. Results and discussion
Synthesis of solasodine acetate 2 started with acetylation of
commercially available diosgenin 5 [17] followed by boron trifluor-
ide etherate/triethylsilane-mediated reductive ring opening of 5/6
spiroketal 12 to stereoselectively give primary alcohol 13 [18]. The
Scheme 2. Initial attempts for solasodine acetate synthesis.

Y. Kou et al. / Steroids 77 (2012) 1069–1074
1073
Scheme 3. Synthesis of solasodine acetate 2.
Scheme 4. A potential reaction mechanism for oxazaspiroketal formation.
Fig. 4. oxazaketal or oxazaspiroketal-containing natural products.
primary amine was used as a key transformation. Solasodine ace-
Acknowledgements
tate 2 has been prepared in 8 steps with an overall yield of 23%.
Oxazaketal or oxazaspiroketal moieties, found in many biologically
active natural products, such as quinocarcin, huperizine-Q, fendler-
idine, and azaspiracid (Fig. 4) have been implicated to be important
for the bioactivities of these natural products. We are currently
applying the hypoiodite-mediated aminyl radical cyclization to
synthesize oxazaspiroketal-containing natural products, and the
results will be reported elsewhere in due course.
This research was kindly supported by Robert A. Welch Founda-
tion (Grant No. F-1741).
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