Direct amination of EF spiroketal in steroidal sapogenins: An efficient synthetic strategy and method for related alkaloids

Article abstract of DOI:10.1016/j.tetlet.2015.10.043

Herein a direct amination of the EF spiroketal in steroidal sapogenins is reported for the first time. This reaction provides a new strategy and method for the synthesis of steroidal alkaloids, which are generally isolated from Chinese medicinal herbs and pharmaceutically attractive. Solasodine, a steroidal alkaloid with good antitumor bioactivities, is synthesized in three steps and 43% overall yield.

Full text of DOI:10.1016/j.tetlet.2015.10.043

Tetrahedron Letters 56 (2015) 6639–6642
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct amination of EF spiroketal in steroidal sapogenins: an efficient
synthetic strategy and method for related alkaloids
⇑
⇑
Jing-Jing Wu, Ran Gao, Yong Shi , Wei-Sheng Tian
The Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein a direct amination of the EF spiroketal in steroidal sapogenins is reported for the first time. This
reaction provides a new strategy and method for the synthesis of steroidal alkaloids, which are generally
isolated from Chinese medicinal herbs and pharmaceutically attractive. Solasodine, a steroidal alkaloid
with good antitumor bioactivities, is synthesized in three steps and 43% overall yield.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 31 August 2015
Revised 10 October 2015
Accepted 13 October 2015
Available online 19 October 2015
Keywords:
Alkaloids
Steroids
Direct amination
Solasodine
Synthetic methods
Steroidal alkaloids are known to have a variety of biological
activities and chemical structures.1 Those with a nitrogen atom
furostanol 10 in high yields10 and the intramolecular redox process
11
to give trace amount of furostanal 11,
both with the E
2
at the C26 on the F ring, such as solasodine (3), tomatidenol
ring saturated. Since the redox process was reversible, the
3
4
1b,5
12
(
4), solanidine (5), and cyclopamine (6),
attract us most,
equilibrium was easily driven to 11 by trapping it with thiol or
1
3
because they are essentially analogues or variants of diosgenin
hydrogen sulfide. The former provided C26–thioacetal 12 or
C26–thioethers 13 in high yields, and the latter directly gave
thiodiosgenin 2 in moderate yields, which is the only example of
the oxygen atom being replaced with a heteroatom in one step.
However, no successful F ring opening with concurrent nitrogen
substitution at the C26, in any form, was reported. This was par-
tially because all such reactions were carried out under acidic con-
ditions where the nitrogen reagents behaved more as bases than as
nucleophiles. Herein we report an efficient and scalable process for
preparing the C26 nitrogen-substituted furostanes.
(1), a steroidal sapogenin we have worked on for two decades
(
Fig. 1). These compounds were also reported and assumed to be
5b,6
closely related in biosynthesis.
We are interested in how
nature creates such molecules and first trying to answer whether
the oxygen atom on the F ring of 1 could directly be replaced
with other heteroatoms.
To replace the oxygen atom, steroidal sapogenins were often
transformed into pseudospirostane-type products on which stan-
dard substitution transformations were then performed. Depicted
in Scheme 1 are several practical methods. In 1940s, Marker
et al. reported the preparation of 7 by heating 1 at 200 °C with
acetic anhydride, and this process has been optimized to lower
The ring opening processes of steroidal sapogenins are essen-
tially the chemistry of spiroketals and are often triggered by Lewis
acids. Based on previous studies, boron trifluoride etherate is the
7
12b,14
the temperature and then used extensively in steroidal industry.
prime choice for Lewis acid.
As for the nitrogen sources,
The Fuchs group reported methods resulting in F ring opening with
amines substituted with electron-withdrawing groups have
lower basicities and could exhibit certain degrees of
nucleophilicities under acidic conditions. Amides and sulfamides
were therefore chosen and tested.
2
differentiated protecting groups at C3 (Ac) and C26 (COCHCl , TFA)
under milder conditions.8 Alternative protocols featuring F ring
opening with concurrent halogenation or sulfuration were also
9
developed by Fuchs and us. Other methods included the reductive
No reactions occurred when diosgenin acetate (1a) was treated
opening of the spiroketal of diosgenin acetate (1a) to give
with BF
etamide. Treating 1a with BF
a complex mixture, delivering four products along with the
unreacted starting material. The products were identified as
C26–methanesulfonamide-substituted furostanes 15a–15c and
3
ÁEt
2
O and amides such as acetamide and trifluoroac-
O and methanesulfonamide gave
3
ÁEt
2
⇑
Corresponding authors. Tel.: +86 21 54925178 (Y.S.), +86 21 54925176
W.-S.T.).
E-mail addresses: shiong81@sioc.ac.cn (Y. Shi), wstian@sioc.ac.cn (W.-S. Tian).
(
http://dx.doi.org/10.1016/j.tetlet.2015.10.043
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

6
640
J.-J. Wu et al. / Tetrahedron Letters 56 (2015) 6639–6642
2
6
26
MsNH
2
2
, BF
3
•OEt
2
H
H
X
HN
CH Cl , rt
2
H
H
O
O
1
a
O
O
NHMs
NHMs
NHMs
H
H
H
H
H
1
5a
15b
H
H
H
H
Ms
OH
O
HO
HO
H
N
diosgenin(1, X = O)
tomatidenol(4)
HN
H
thiodiosgenin(2, X = S)
solasodine(3, X = NH)
26
O
1
5c
H
H
H 15d
O
N
H
Scheme 2. Direct amination of the diosgenin acetate (1a).
H
2
6
H
H
H
H
HO
HO
solanidine(5)
cyclopamine(6)
Table 1
Conditions for F ring opening
a
Figure 1. Chemical structures of diosgenin and several steroidal alkaloids.
Entry MsNH BF
2
3
ÁEt
2
O
15ab
(%)
15bb
(%)
15cb
(%)
15db
(%)
Yieldc
(%)
(
equiv)
(equiv)
the azodiosgenin mesylate 15d (Scheme 2). We then found that the
overall yields of the products were improved upon increasing the
1
2
3
4
5
6
7
8
9
2
3
4
6
4
4
4
4
4
4
8
8
8
8
3
4
4
4
4
4
18
28
29
36
30
29
10
9
6
2
6
7
4
6
0
6
6
7
22
14
35
26
20
30
52
57
36
38
6
17
16
18
13
18
6
12
5
11
52
61
86
87
67
83
68
84
81
84
amounts of BF
Table 1. The optimum condition involved the use of 4 equiv of
BF O and 4 equiv of methanesulfonamide at ambient tempera-
ÁEt
ture, giving an overall yield of 83% (entry 6).
3 2
ÁEt O and methanesulfonamide, as displayed in
3
2
15
d
e
f
Although the desired nitrogen atom has been successfully
introduced, purifying the four products was troublesome and
converting them to one product was preferable. Altering the exper-
imental parameters (reaction time, temperature, and solvent) did
not gave a cleaner reaction system.16 Since 15d already has the
form of azo-spiroketal, converting 15a–15c to 15d would allowed
us to reach an efficient two-step synthesis of solasodine (3), the
first target natural product of this research. However, treating
34
28
g
10
a
Unless otherwise noted, the reaction was conducted on the 0.50 mmol scale in
DCM (5 mL) at 25 °C for 5–8 h.
b
Yields of isolated products.
The overall yields of four products.
The reaction was allowed to stand at rt for 48 h.
The crude was not purified immediately after workup but kept for 48 h before
c
d
e
1
5a–15c with various acids and electrophiles (TMSCl, TMSOTf,
purification.
f
CSA, TsOH, CF CO H, HOAc; NBS, NIS) failed to improve the yield
3
2
The reaction was conducted in DCM at reflux for 2 h.
The reaction was conducted in 1,2-dichloroethane for 8 h, and the reaction in
chloroform gave a similar result.
g
of 15d, resulting in only a more complex mixture. Since both
isomerization of the exocyclic double bond in 15b and dehydration
of the hemiacetal in 15c would lead to 15a, we reasoned, the
reaction could be simplified by these transformations. Pleasingly,
we found that keeping the solution of a mixture of 15a–15d in
toluene at reflux converted not only 15b and 15c but also 15d to
a. BF •OEt (4 equiv)
1
5a, thus delivering 15a in 76% yield.
3
2
H
O
S
CH
2
Cl
2
, rt, 8 h
1
a+
R
NH2 b. PhMe,reflux, 5-8 h
O
O
2
NHSO R
(
4 equiv)
H
1
5a-26
H
forming
pseudospirostans
R =
O
2
6
OCOR
H
Me
R = Me (7), CF
3
2
(8), CHCl (9)
Me
OMe
Br
20
73%
H
2
6
H
15a
16
17
18
19
78%
7
6%
82% 82%(10 g) 81%
O22F
O
redox or
O 26
H
reduction
Y
E
X
H
Cl
2
O N
1
6
1
0 X = OH, Y = H
H
11 X = Y = O
1
2 XY = -SCH CH S-
Cl
NO
22
51%
diosgenin(1) or
diosgeninacetate(1a)
2
2
2
21
23
75%
24
53%
25
36%
26
63%
H
7
7%
substitution
at C26
O
failedreagents:
SO NH
2
6
R
2
2
2 2
SO NH
H
F
3
C
H
2
N
2
H N
2
SO NH
2
1
1
3 R = SPh,SBn
4 R = I, Br, Cl
O
O
This work: = NHX
SO NHNH
2
2
Me
NH
2
F
3
C
NH
2
Scheme 1. Methods have been developed to open the F ring of the spiroketal
system of steroidal sapogenins.
Scheme 3. Scope of nitrogen sources.

J.-J. Wu et al. / Tetrahedron Letters 56 (2015) 6639–6642
6641
Failed conditionsforremoving Ms on 15a: Na, i-PrOH, reflux; Red-Al,
O
X
H
X
H
H
toluene,reflux; LiAlH
4
, THF, rt to reflux;Mg, MeOH, reflux; CsF, celite, 120°C
H
Y
H
Y
H
ring
O
R = Ms to
O
opening
5,6-dihydro-36
H
H
NHMs
H
H
O
H
O
AcO
AcO
Na, naphthalene
53%
R = Ts
H
NH2
H
NHR
H
H
tigogeninacetate(27): X = Y = H
hecogeninacetate(28): X = Y = O
rockogeninacetate(29): X = OAc; Y = H
30 (68%): X = Y = H
31 (69%): X = Y = O
32 (69%): X = OAc; Y = H
H
HO
1
5a or 17
36
Failed conditionsforremoving Ts on 17: Mg/MeOH; NaH, 1,3-propanediamine;
NaNH
2
; LiNH
2
; Na, NH
3
(l); HBr, HOAc; TMSCl, NaI; Red-Al, toluene,reflux.
Scheme 4. Direct amination of other steroidal sapogenins.
Ms
N
n-BuLi, 0 °C, 15 min
H
H
2
then O , rt, 3 h, 44%
MsNH2
HN
O
O
H
F
3
B
H
ring F
H
H
15d
H
O
opening
OBF
3
O
1
2 3 2
. TsNH , BF •Et O, 4 h
O
O
H
2. Na, naphthalene,5 h
3. TMSCl, DCM, rt, 7 h
O
solasodine(3)
H
34
internalredox
[1.5]-H shift)
H
1a
10 mmol scale
(
4
3% overall yield
ring F opening
1a
with C26-N
substitution
11
MsNH
2
Scheme 6. Synthesis of steroidal alkaloid solasodine (3).
MsHN
Ms
HN
internal
redox
2
0
2
3
H
C26–O bond directly to open the F ring (red arrows). On the other
hand, treating 11 with BF O could also form 1a and then give
O
O
3
ÁEt
2
3
3
H
35
15a from 1a, therefore, the observation of converting 11 to 15a
did not necessarily support the latter pathway. The precise mech-
anism remains interesting for further investigations.
H
loss of
C20-H
loss of
C23-H
aqueous
workup
cyclization
We then applied the established reaction in the synthesis of
solasodine (3). We found that removing the sulfonyl groups were
low-yielding after screening various conditions (Scheme 6). The
1
5a
15b
15c
15d
1
9
MsNH
CH Cl
2
, BF
3
•Et
2
O
MsNH
2
, BF
3
•Et
2
O;
2
2
, rt, 48 h
thentoluene,reflux
best results were: deprotection of 15d (n-BuLi, THF, 0 °C, then
1
0
15a
11
1
9g
6
7%
O
2
)
gave solasodine (3) in 44% yield and deprotection of 17
(
Na, naphthalene, THF, rt) gave the desired -NH enol ether 36
x
2
Scheme 5. Plausible mechanisms for amination of diosgenin acetate 1a.
in 53% yield. Finally, on the 10 mmol scale, 3 was prepared in an
overall yield of 43% through a three-step process: opening the F
ring with C26 substituted, removing the tosyl and acetyl groups
with Na/naphthalene, and re-closing the F ring with TMSCl. The
spectroscopic properties of the synthetic 3 are consistent with
those reported. This process constituted the shortest route to this
interesting steroidal alkaloid (two steps via 15d, three steps via
1
We then applied the reaction to other sulfonamides and
obtained similar results (Scheme 3).17 Benzenesulfonamides that
were not substituted or para-substituted with alkyl, methoxyl,
and halogen groups all worked well, delivering furostanes 17–21
in good yields. The ortho-substituents lowered the yields slightly.
Strong electron-withdrawing substituents such as nitro group
reduced the yields by ca. 20% (22 and 25). Using phenylmethane-
sulfonamide as nucleophile gave 26 in 63% yield. The reaction
was easily scaled up and was performed on the 10 g scale to give
9b
9b,20
7).
In conclusion, the direct C26 amination by nitrogen nucle-
ophiles with (formation of 15a) or without (formation of 15d) F
ring opening of steroidal sapogenins was realized for the first time.
The success of this process relies on the compatibility of sulfon-
amides with Lewis acids. This method enriches the tactical choices
of using the steroidal sapogenins and enabled an efficient, three-
step synthesis of solasodine. Applying this strategy to non-steroid
substrates and probing the possible biosynthetic transformations
among steroidal alkaloids are ongoing in this laboratory.
1
7 in 82% yield. The reaction was also applied on the acetates of
other steroidal sapogenins 27–29 to give the 30–31 in good yields
Scheme 4).
(
Two possible pathways of forming 15a–15d were illustrated in
Scheme 5. One path is that Lewis acid activation of 1a permits the
C26 substitution with F ring opening to generate 33, which could
be easily transformed to 15a–15d. On the other path, Lewis acid
could also trigger an internal redox process ([1.5]-H shift) and
the resultant aldehyde 11 reacts with methanesulfonamide to gen-
erate N-mesylimine 35 which undergoes another internal redox
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.10.
0
1
8
process to form 33, rebuilding the oxidation states of C22 and
C26. Although the former path provided a simple and reasonable
explanation to the reaction outcome, we soon found C26–OH alone
43.
References and notes
resisted being substituted with MeSO
2
NH
2
under our conditions.
NH
2
Upon treating with 4 equiv of BF O and 4 equiv of MeSO
ÁEt
3 2
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3 2
3
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.
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5
.
.
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4
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