Asymmetric synthesis of (-)-solanidine and (-)-tomatidenol

Article abstract of DOI:10.1039/d0ob00457j

A concise asymmetric synthesis of two naturally occurring seco-type cholestane alkaloids (-)-solanidine and (-)-tomatidenol from (-)-diosgenin with a linear reaction sequence of 12 steps and 13 steps, respectively, is reported. The synthetic strategy includes the highly controlled establishment of highly functionalized octahydroindolizine ((-)-solanidine) and 1-oxa-6-azaspiro[4.5]decane ((-)-tomatidenol) cores with five stereocenters, respectively, from (-)-diosgenin, featuring two stereoselective cascade transformations including a modified cascade ring-switching process of furostan-26-acid to open the E-ring of (-)-diosgenin and a cascade azide reduction/intramolecular reductive amination to close the E- and F-rings of (-)-solanidine and (-)-tomatidenol. This work should enable further explorations of chemical and biological spaces based on solanidine, tomatidenol and related natural products.

Full text of DOI:10.1039/d0ob00457j

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DOI: 10.1039/D0OB00457J
ARTICLE
Asymmetric Synthesis of (-)-Solanidine and (-)-Tomatidenol
Yun Wang,a, b Guanxin Huang,a Yong Shi,c Wei-sheng Tian,c Chunlin Zhuang, a, b, * and Fen-
Er Chen a, b, d,
*
Received 00th January 20xx,
Accepted 00th January 20xx
A concise asymmetric synthesis of two naturally occurring seco-type cholestane alkaloids (-)-solanidine and (-)-tomatidenol
from (-)-diosgenin with a linear reaction sequence of 12 steps and 13 steps, respectively is reported. The synthetic strategy
includes the highly controlled establishment of highly functionalized octahydroindolizine ((-)-solanidine) and 1-oxa-6-
azaspiro[4.5]decane cores ((-)-tomatidenol) with five stereocenters, respectively from (-)-diosgenin, featuring two
stereoselective cascade transformations including a modified cascade ring-switching process of furostan-26-acid to open E-
ring of (-)-diosgenin and a cascade azide reduction /intramolecular reductive amination to close E and F-rings of (-)-solanidine
and (-)-tomatidenol. This work should enable further explorations of chemical and biological spaces based on solanidine,
tomatidenol and related natural products.
DOI: 10.1039/x0xx00000x
investigation of their bioactive and structure-activity relationship.
Herein, we report our efforts that culminated in an improved
asymmetric synthesis of (-)-solanidine (1) and first formal
asymmetric synthesis of (-)-tomatidenol (2) from commercially
available (-)-diosgenin (5) in large bulk in China.
Introduction
(-)-Solanidine (1) and (-)-tomatidenol (2) represent two types of seco-
cholestane alkaloids isolated from various potato species of solanum
family including solanum demissum L.,[1] solanum acaule L.,[2]
solanum tubersum L.,[3] solanum spirale L.,[4] and solanum dulcamara
L.[5] etc (Figure 1), mainly present as glycosides. The former has
proven to inhibit proliferation and induce apoptosis in various types
of cancer cells in vitro,[6] and the latter has been reported to possess
antimicrobial,[7] antifungal,[8] etc and are used as natural insect
deterrents.[9] Structurally, the seco-type cholestane alkaloids 1 and 2
(S)
H
(S)F
N
H
E
(R)F (S)
E
N
H
O
H
H
H
H
H
H
HO
HO
1
(-)-Solanidine (
)
2
)
(-)-Tomatidenol (
H
(R)
H
possess
an
unique
octahydroindolizine
and
1-oxa-6-
HN
E
(R)F
H
(R)F
E
(S)
azaspiro[4.5]decane ring systems with five stereocenters,
respectively that lie within a complex cholestane skeleton.
N
H
O
H
H
H
H
H
Somewhat surprisingly, there are only three reports of synthesis of
the natural alkaloid 1 including the Schreiber’s four-step approach
starting from naturally occurring product 2,[10] the Pelletier’s three-
step route[11] via the reduction cleavage of either isorubijervine
mono tosylate or monoidodide from isorubijervine, an alkaloid of
veratrum album and veratrum viride,[12] and recent Tian’s eight-step
synthesis by an intramolecular Schmidt reaction of chiral azido diol
from (-)-diosgenin (5).[13] There is no report on the strategy and
method for synthesis of natural alkaloid 2.[14] Considering the scare
synthetic achievements of seco-cholestane alkaloids and in
connection with our long-time research interests to steroidal
alkaloids,[13-15] we initiated a long-term research program aiming to
the synthesis of this type of natural products to enable further
HO
HO
H
4
(-)-Demissidine ( )
3)
(-)-Solasodine (
(R)
O
F
(R)
E
O
H
H
H
HO
5
(-)-Diosgenin (
)
Figure 1. Structures of (-)-solanidine (1), (-)-tomatidenol (2) and (-)-solasodine (3),
(-)- demissidine (4) and (-)-diosgenin (5).
Results and discussion
a. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Fudan
University, Shanghai 200433, China
Our synthetic plan for (-)-solanidine (1) and (-)-tomatidenol (2) is
outlined in Scheme 1. (-)-Solanidine (1) and (-)-tomatidenol (2) were
envisioned to be generated from azidodiketone 6 by construction of
octahydroindolizine and 1-oxa-6-azaspiro[4.5]decane units via azide
reduction/ stereoselectively intramolecular reductive cascade
amination, and stereoselective reduction of the C16-ketone function
followed by azide reduction/ intramolecular hemispiroketetal
cascade cyclization, respectively. The azidodiketone 6 could be
E-mail: rfchen@fudan.edu.cn (F.-E. Chen); zclnathan@163.com (C.-L. Zhuang)
b. Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs,
Shanghai 200433, China
c. Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China.
d. Institute of Pharmaceutical Science and Technology, Zhejiang University of
Technology, 18 Chao Wang Road, 310014, Hangzhou, China
Electronic Supplementary Information (ESI) available: [NMR spectra]. See
DOI: 10.1039/x0xx00000x
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obtained from the corresponding triol 7 by SN2 azido nucleophilic The next stage of the synthesis involved an intramolecular ring-
View Article Online
DOI: 10.1039/D0OB00457J
displacement, selective tosylation and Swern oxidation. The triol 7 switching process to assemble chiral six-membered lactone ring and
would be derived from C16α-iodolactone 8 by nucleophilic C16α-I bond of C16α-iodolactone 8 (Table 1) in according with similar
15a, 15c]
substitution with CsOAc followed by C25 epimerization and C16-OAc reaction in our prior art.[13,
The first attempt at an
reduction/ deacetylation. The six-membered lactone with two intramolecular ring-switching reaction of 9 with 3 equiv of TBAI as
stereocenters and C16α-I bond of 8 could conveniently be nucleophile under TFAA (activator)-free condition resulted in no
constructed using a modified tetrabutylammonium iodide (TBAI)- reaction and 95% of recovery unreactive 9 (entry 1). However,
catalyzed trifluoroacetic anhydride(TFAA)-LiI promoted cascade ring- employing 5 equiv of TBAI as nucleophile in the reaction of 9 in the
switching process of furostan-26-acid 9, which could be originated presence of 3 equiv of TFAA in CH2Cl2/MeCN provided the desired
from (-)-diosgenin (5) through a route largely similar to the one C16α-iodolactone 8 for 24 h in 67% yield along with macrolide
previously used in this laboratory in the asymmetrie of (-)-solasodine product 12 in 10% yield after silica gel column chromatography
(3), (-)- demissidine (4) and other related cholestane alkaloids[15]
.
(entry 2).
Scheme 1. Retrosynthetic analysis for (-)-solanidine (1) and (-)- Table 1. Synthesis of C16 α-iodolactone 8 by the ring-switching
tomatidenol (2).
reaction of 9 under different conditions
H
O
H
O
I
(R)
(S)
(R)
H
N
(R)
N3
H
O
H
H
H
(S)
H
HO
H
H
H
O
H
TBDPSO
1
(-)-Solanidine (
)
8
(R)
H
H
(R)
(S)
O
HO2C
TFAA (3 equiv),
CH2Cl2/MeCN (4:1)
TBDPSO
H
6
(S)
iodide, 0 to rt
H
H
℃
N
O
H
I
TBDPSO
H
H
9
H
H
O
H
HO
2
(-)-Tomatidenol (
)
O
H
H
12
O
OH
TBDPSO
O
OH
(R)
H
(S)
H
(R)
(R)
H
I
H
OH
Entry
Iodide (equiv)
TBAI [a] (3)
TBAI (5)
Time (h)
Yield(%)[b] (8/12)
none
H
H
H
H
TBDPSO
TBDPSO
8
7
1
2
3
4
5
6
7
4
24
3.5
4
67/10
(R)
H
LiI (3)
72/13
O
(R)
(R)
(R)
O
HO2C
H
O
NaI (3)
71/14
H
H
H
H
H
NH4I (3)
4
70/13
TBDPSO
HO
9
5
(-)-Diosgenin ( )
LiI/TBAI (3/0.5)
LiI/TBAI (4/0.5)
4
72/13
Our synthesis began with efficient synthesis of furostan-26-acid 9,
and its synthesis route is depicted in Scheme 2, starting from (-)-
diosgenin (5), the (-)-diosgenin TBDPS ether 10 was be easily
prepared in our multigram scale following the known procedure.[16]
Then, regioseletive spiroketal cleavage of the resulting crude 10
using Et3SiH/BF3·Et2O reduction[17] at room temperature
stereospecifically delivered primary alcohol 11 without purification
and further underwent Jones oxidation to yield the corresponding
furostan-26-acid 9 in 73% overall yield over three steps.
4
74/8
[a] No activator TFAA was added. [b] Yield of isolate after silica gel column
chromatography.
Armed with this result, we queried whether we might optimize this
transformation to further decrease the formation of the by-product
12. The use of other nucleophiles such as 3 equiv of LiI, NaI, NH4I and
LiI/TBAI (3/0.5 equiv) (entries 3-6) led to the disappointing reaction
results analogous to that of TBAI as in entry 1. To our delight, simply
switching the nucleophile for this transformation to LiI (4 equiv) and
TBAI (0.5 equiv) afforded 8 in 74% yield, only 8% of 12 was isolated
(entry 7).
Scheme 2. Synthesis of furostan-26-acid 9
(R)
(R)
O
O
(R)
(R)
16
ref
O
O
H
H
After accomplishing C16α-iodolactone 8, the next stage was set for
the installation of C16β-hydroxyl functionality through the
nucleophilic substitution of C16α-I in 8 by a suitable acetate (Scheme
3). Initially, nucleophilic substitution using KOAc in DMF at 60 °C for
15 h restore the C16β-O functional group to give C16β-ester 13 in 83%
yield along with 16% of the thermodynamically favored elimination
product 14 (Table 2, entry 1). To solve this problem, we elected to
conduct this transformation using CsOAc as the nucleophiles. As
expected, heating 8 with CsOAc in DMF at 60 °C for 15 h gave rise to
C16β-ester 13 in 91% yield, accompanied by a negligible amount of
H
H
H
H
HO
TBDPSO
5
10
(-)-Diosgenin (
)
Et3SiH, BF3· Et2O
ClCH2CH2Cl, rt, 3h
Jones reagent, CH3CN/CH2Cl2
0℃, 3h
H
H
73% for 3 steps
(R)
(R)
(R)
(R)
O
O
H
H
H
HO2C
OH
H
H
H
TBDPSO
TBDPSO
9
11
2 | J. Name., 2012, 00, 1-3
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14 for ready C25 epimerization reaction (entry 2). Consistent with When performing the reaction using NaBH4 and NiCl2·V6iHew2OArtiinclemOinxleinde
15a]
our previous studies,[13,
treating 13 with K2CO3 in MeOH THF and MeOH at 0°C, the yield of 17 was increased to 79%. The final
DOI: 10.1039/D0OB00457J
underwent C25-epimerization followed by LAH reduction delivered desilylation proceeded without incident. The TBDPS group in 17 was
16, 22, 26-triol 7 in 92% yield over the two steps.
clearly removed by treatment of TBAF in THF at 50 °C for 2 h, (-)-
solanidine (1) was obtained in essentially quantitative yield[15a]
(Scheme 5). The spectroscopic data (1H NMR, 13C NMR, HRMS and
specific rotation of the synthetic product) are in excellent agreement
with those reported.[13,18]
Scheme 3. Synthesis of 16, 22, 26-triol 7
O
O
(R)
H
(R)
Scheme 4. Synthesis of azidodiketone 6.
MOAc,DMF
H
I
50
℃,15
h
H
H
OH
OTs
TBDPSO
OH
OH
25
25
8
(S)
(S)
H
H
TsCl, Et3N, DMAP
(R)
(R)
CH2Cl2, rt, overnight
16
16
H
OH
H
OH
O
O
H
H
H
H
O
O
TBDPSO
TBDPSO
(R)
(R)
7
15
H
(R)
(R)
H
H
OAc
NaN3, DMF,
60 , 6 h
90% for 2 steps
H
H
℃
H
H
TBDPSO
TBDPSO
13
14
N3
N3
O
Table 2. Results of reactions using MOAc
25
OH
(S)
(S)
25
H
H
1. (COCl)2, DMSO,
CH2Cl2, -78 , 1 h
2. Et N, 0 rt, 30 min
℃
to
73%
16 OH
Yield (%)[a]
13/14
H
16 O
entry
MOAc
℃
H
3
H
H
H
H
TBDPSO
TBDPSO
6
16
1
2
KOAc
83/16
1.K2CO3,MeOH,
50
℃,5h
2.LAH,THF,
to rt
[b]
CsOAc
91/0
The synthesis of (-)-tomatidenol (2) is described in Scheme 6.
Reduction of 6 with NaBH4 in THF/methanol at room temperature
gave the desired hemiketal 18 in 61% yield along with 22% of
azidoalcohol 22-epi-16. After separation, the undesired azidoalcohol
22-epi-16 was oxidized back to the azidodiketone 6 in 75% yield by
Swern oxidation and was recycled. The hemiketal 18 was treated
with iodotrimethylsilane,[19] (in situ prepared by trimethyl
chlorosilane (TMSCl) and NaI) in MeCN to generate (-)-tomatidenol
TBDPS ether 19 through the cascade azide reduction/stereoselective
hemispiroketal cyclization, which was directed cleaved by TBAF in
THF to afford the expected (-)-tomatidenol (2) in 75% yield. The
0℃
overnight
92% for 2 steps
[a] Isolate yield. [b] Almost no visible trace of 14.
OH
OH
(S)
25
H
(R)
16
H
OH
H
H
TBDPSO
7
synthetic product exhibited identical spectroscopic data (1H NMR, 13
NMR, HRMS and IR) with those of we previously synthesized.[14]
C
Prior to further construction of the E- and F-ring of 1 and 2, we
focused on forming azidodiketone framework through a three-step
sequence of tosylation of C26-OH in 7 azide displacement to tosylate
15 and Swern oxidation of C16β-OH in 16 as illustrated in Scheme 4.
Regioselective tosylation of the C26-OH in 7 with p-toluene sulfonyl
chloride (p-TsCl) and Et3N generated a tosylate 15 to be azide
displacement by NaN3, providing the corresponding azidodidiol 16 in
90% yield over the two steps. Oxidation to 16 proved to be less
straightforward than anticipated. Oxidation using Dess-Martin
periodinane (DMP) led to formation of a complex mixture of
products. Pleasingly, treatment of 16 with large excess of oxalyl
chloride (8 equiv) and DMSO (12 equiv) in CH2Cl2 at -78°C for 2 h for
Swern oxidation of the exposed C16β-OH and C22-OH efficiently
supplied azidodiketone 6 in 73% yield.
Scheme 5. Complete the synthesis of (-)-solanidine (1)
Raney Ni, H , MeOH, 40
2
4 h
℃,
64%
N3
O
H
25
(S)
H
H
NaBH4, NiCl2 6H2O
(R)
(S)
THF, MeOH, 0
2.5 h
℃,
16 O
N
H
H
79%
H
H
H
H
TBDPSO
TBDPSO
6
17
TBAF,
THF, 50
2 h
With the key intermediate 6 in hand, we directed our attention to
the construction of E- and F-ring for the synthesis of (-)-solanidine (1)
and (-)-tomatidenol (2). One-pot three-step transformation (namely,
azide reduction and double reductive amination) using Raney Ni-
catalyzed hydrogenation was first tested on the azidodiketone 6. In
this event, the treatment of 2 with Raney Ni in MeOH at 40 °C
produced the desired (-)-solanidine (1) TBDPS ether 17 in 64% yield.
℃,
99%
H
H
(R)
(S)
N
H
H
H
HO
1
(-)-Solanidine ( )
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J. Name., 2013, 00, 1-3 | 3
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MHz, CDCl3) δ 7.63-7.70 (m, 4H), 7.33-7.48 (m, 6H), 5.14 (d, J = 5.0 Hz, 1H), 4.33
Scheme 6. Complete the synthesis of (-)-tomatidenol (2).
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DOI: 10.1039/D0OB00457J
(td, J = 7.7, 5.1 Hz, 1H), 3.50-3.60 (m, 1H), 3.32-3.40 (m, 1H), 2.47-2.62 (m, 1H),
N3
2.29-2.43 (m, 1H), 2.10-2.22 (m, 1H), 1.88-2.05 (m, 2H), 1.54-1.83 (m, 11H), 1.37-
1.51 (m, 3H), 1.25-1.36 (m, 1H), 1.18-1.22 (m, 2H), 1.20 (d, J = 6.9 Hz, 3H), 1.08 (s,
9H), 1.02 (s, 3H), 1.00 (d, J = 6.7 Hz, 3H), 0.82-0.93 (m, 2H), 0.80 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 181.9 (C), 141.4 (C), 135.9 (2CH), 135.9 (2CH), 134.93 (C), 134.9
(C), 129.6 (CH), 129.5 (CH), 127.6 (2CH), 127.6 (2CH), 121.0 (CH), 90.3 (CH), 83.6
(CH), 73.3 (CH), 65.0 (CH), 57.1 (CH), 50.1 (CH), 42.6 (CH2), 40.8 (C), 39.6 (CH), 39.5
(CH2), 38.1 (CH), 37.3 (CH2), 36.7 (C), 32.3 (CH2), 32.1 (CH2), 32.0 (CH2), 31.7 (CH),
31.4 (CH2), 31.1 (CH2), 27.1 (3CH3), 20.8 (CH2), 19.6 (CH3), 19.3 (C), 19.0 (CH3), 17.3
(CH3), 16.5 (CH3); HRMS (ESI) m/z calcd for C43H60O4SiNa [M+Na]+: 691.4153, found:
691.4139.
OH
(S)
H
℃
1. (COCl)2, DMSO, CH2Cl2, -78 , 1 h
2. Et N, 0
rt, 30 min
℃
to
3
H
OH
(22%)
OH
75%
H
H
TBDPSO
NaBH4, THF, MeOH
N3
22-epi-16
O
(S)
H
rt 1h
,
H
O
H
H
H
(S)
O
TBDPSO
H
6
N3
H
H
TBDPSO
18
(61%)
TMSCl, NaI, rt, 4h
(S)
(S)
Compound (8) and Compound (12)
(S)
(S)
To a solution of 9 (10 g, 15 mmol) and lithium iodide (8 g, 60 mmol, 4 equiv) and
TBAI (2.76 g, 7.5 mmol, 0.5 equiv) in dry CH2Cl2/CH3CN (100 mL/25 mL) was added
TFAA (6.3 mL, 45 mmol, 3 equiv) at 0 °C. The resulting mixture was vigorously
stirred at ambient temperature for 4 h. The mixture was quenched with saturated
aqueous NaHCO3 and saturated aqueous Na2S2O3, and extracted with CH2Cl2 (3×50
mL). The combined organic layers were washed with brine, dried over sodium
sulfate, filtered, and concentrated in vacuo. The crude was chromatographed on
silica gel (petroleum ether/EtOAc: 20/1-8/1) to give 8 (8.6 g, 74%) as a white foam
and 12 (933 mg, 8%) as a yellow foam. 8: [α]D25 -33.8 (c 1.09, CHCl3); IR (cm-1): 2936,
2897, 2854, 1736, 1589, 1474, 1187, 1110, 1073, 706, 511; 1H NMR (400 MHz,
CDCl3) δ 7.64-7.72 (m, 4H), 7.33-7.45 (m, 6H), 5.11 (d, J = 5.0 Hz, 1H), 4.71 (dt, J =
11.5, 2.8 Hz, 1H), 4.04-4.10 (m, 1H), 3.49-3.59 (m, 1H), 2.59-2.73 (m, 1H), 2.27-2.38
(m, 1H), 1.92-2.27 (m, 7H), 1.80-1.92 (m, 2H), 1.63-1.74 (m, 2H), 1.25-1.63 (m, 10H),
0.74-0.91 (m, 1H), 1.23 (d, J = 6.8 Hz, 3H), 1.06 (s, 9H), 0.97 (s, 3H), 0.94 (d, J=6.7
Hz, 3H), 0.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 176.7 (C), 141.4 (C), 135.9 (2CH),
135.9 (2CH), 134.9 (C), 134.8 (C), 129.6 (CH), 129.6 (CH), 127.6 (2CH), 127.6 (2CH),
120.6 (CH), 79.7 (CH), 73.2 (CH), 64.8 (CH), 53.4 (CH), 49.7 (CH), 45.3 (C), 42.5 (CH2),
41.9 (CH2), 39.7 (CH2), 39.4 (CH), 37.2 (CH2), 36.5 (C), 33.2 (CH), 31.9 (CH2), 31.7
(CH2), 30.6 (CH), 28.8 (CH), 27.1 (3CH3), 25.2 (CH2), 20.9 (CH2), 20.8 (CH2), 19.5 (CH3),
19.3 (C), 16.5 (CH3), 13.9 (CH3), 12.6 (CH3); HRMS (DART) m/z calcd for C43H63NO3ISi
[M+NH4]+: 796.3616, found: 796.3622. 12: [α]D25 -52.6 (c 1.00, CHCl3); IR (cm-1):
2934, 2856, 1731, 1459, 1110, 759, 702, 510; 1H NMR (400 MHz, CDCl3) δ 7.65-7.72
(m, 4H), 7.32-7.45 (m, 6H), 5.30 (td, J=8.4, 6.0 Hz, 1H), 5.11 (d, J = 5.3 Hz, 1H), 4.23-
4.31 (m, 1H), 3.48-3.58 (m, 1H), 2.40-2.54 (m, 1H), 2.00-2.39 (m, 6H), 1.83-1.98 (m,
2H), 1.49-1.75 (m, 6H), 1.33-1.49 (m, 6H), 1.21-1.33 (m, 1H), 1.18 (d, J = 7.1 Hz, 3H),
℃
TBAF, THF, 50
overnight
N
N
O
H
O
H
H
H
75% for 2 steps
TBDPSO
H
H
H
H
HO
2
(-)-Tomatidenol ( )
19
Experimental
General Methods. All reactions sensitive to air or moisture were performed in
flame-dried flasks with rubber septum under a positive pressure of argon
atmosphere, unless otherwise noted. Air and moisture-sensitive liquids and
solutions were transferred via syringe and stainless-steel cannula. Yields refer to
chromatographically and spectroscopically (1H NMR) homogeneous materials,
unless otherwise stated. Reactions were monitored by thin-layer chromatography
(TLC) carried out on silica gel plates using an ethanolic solution of phosphomolybic
acid, and heat as developing agents. NMR spectra were recorded on 400 MHz
instrument and calibrated using residual undeuterated solvent as an internal
reference [1H NMR: CHCl3 (7.26); 13C NMR: CDCl3 (77.16)]. The following
abbreviations were used to explain the multiplicities: s = singlet, d = doublet, t =
triplet, q = quartet, br = broad.
Compound (9)
To a solution of diosgenin (5, 10.0 g, 24 mmol) in dry DMF (60 mL) were added
imidazole (4.93 g, 72 mmol, 3 equiv) and then TBDPSCl (9.4 mL, 36 mmol, 1.5
equiv). The resulting mixture was stirred at room temperature for 2 h. The mixture
was quenched with water and extracted with EtOAc (3×50 mL). The combined
organic layers were washed with water and brine, dried over sodium sulfate,
filtered, and concentrated in vacuo. The crude and Et3SiH (7.7 mL, 48 mmol, 2
equiv) were dissolved in dry ClCH2CH2Cl (65 mL), and boron trifluoride etherate
(9.1 mL, 72 mmol, 3 equiv) was added dropwise at 0 °C. The resulting mixture was
warmed to room temperature and stirred for 3 h. The mixture was quenched with
saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×50 mL). The combined
organic layers were washed with brine, dried over sodium sulfate, filtered, and
concentrated in vacuo. The crude was dissolved in CH3CN (160 mL) and CH2Cl2 (30
mL) was added Jones reagent (2.6 M, 17 mL, 48 mmol, 2 equiv) dropwise at 0 °C.
The resulting mixture was stirred at 0 °C for 2 h and was quenched with i-PrOH and
filtered. The filtrate was concentrated in vacuo and diluted with EtOAc (200 mL),
washed with water and brine, dried over sodium sulfate, filtered, and concentrated
in vacuo. The crude was chromatographed on silica gel (petroleum ether/EtOAc:
2/1) to give 9 (11.8 g, 73% for 3 step) as a white foam. [α]D26 -47.3 (c 0.65, CHCl3);
IR (cm-1): 3070, 2932, 2898, 2856, 1706, 1110, 1088, 740, 702, 509; 1H NMR (400
1.07 (d, J=10.0 Hz, 3H), 1.06 (s, 9H), 0.99 (s, 3H), 0.91 (s, 3H), 0.75-0.89 (m, 2H); 13
C
NMR (100 MHz, CDCl3) δ 178.2 (C), 141.4 (C), 135.9 (2CH), 135.9 (2CH), 134.9 (C),
134.9 (C), 129.6 (CH), 129.6 (CH), 127.6 (2CH), 127.6 (2CH), 120.8 (CH), 76.2 (CH),
73.3 (CH), 58.5 (CH), 54.1 (CH), 49.8 (CH), 42.9 (CH), 42.6 (CH2), 41.9 (C), 41.6 (CH),
39.7 (CH2), 39.1 (CH2), 37.2 (CH2), 36.6 (C), 34.1 (CH2), 33.0 (CH2), 32.0 (CH2), 31.9
(CH2), 31.2 (CH), 30.7 (CH), 27.2 (3CH3), 24.2 (CH3), 20.8 (CH2), 19.6 (CH3), 19.3 (C),
18.6 (CH3), 13.3 (CH3); HRMS (DART) m/z calcd for C43H63NO3ISi [M+NH4]+:
796.3616, found: 796.3601.
Compound (13)
To a solution of 8 (3.00 g, 3.85 mmol) in dry DMF (15 mL) was added CsOAc (3.70
g, 19.3 mmol, 5 equiv). The resulting mixture was stirred at 60 °C for 15 h, and was
4 | J. Name., 2012, 00, 1-3
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quenched with waterand extracted with EtOAc (3×50 mL). The combined organic
layers were washed with water and brine, dried over sodium sulfate, filtered, and
concentrated in vacuo. The residue was chromatographed on silica gel (petroleum
ether/EtOAc: 5/1) to give 13 (2.51 g, 91%) as a white foam. [α]D24 -22.8 (c 1.58,
CHCl3); IR (cm-1): 2934, 1738, 1241, 703, 510; 1H NMR (400 MHz, CDCl3) δ 7.65-7.69
(m, 4H), 7.32-7.43 (m, 6H), 5.10 (d, J = 5.0 Hz, 1H), 5.06-5.17 (m, 1H), 4.12-4.22 (m,
1H), 3.45-3.58 (m, 1H), 2.50-2.60 (m, 1H), 2.41-2.49 (m, 1H), 2.28-2.38 (m, 2H),
2.01-2.17 (m, 1H), 1.93-2.08 (m, 3H), 2.02 (s, 3H), 1.80-1.92 (m, 1H), 1.55-1.74 (m,
6H), 1.34-1.55 (m, 6H), 1.19 (d, J = 6.8 Hz, 3H), 1.10-1.17 (m, 2H), 1.05 (s, 9H), 1.03-
1.09 (m, 2H), 1.00 (d, J = 7.1 Hz, 3H), 0.89 (s, 3H), 0.78-0.86 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 176.6 (C), 171.0 (C), 141.5 (C), 135.9 (2CH), 135.9 (2CH), 134.9 (C),
134.9 (C), 129.6 (CH), 129.6 (CH), 127.6 (2CH), 127.6 (2CH), 120.7 (CH), 79.0 (CH),
74.3 (CH), 73.3 (CH), 55.5 (CH), 54.8 (CH), 50.0 (CH), 43.0 (C), 42.5 (CH2), 39.7 (CH2),
37.2 (CH2), 36.6 (C), 35.3 (CH2), 33.7 (CH), 33.1 (CH), 31.9 (CH2), 31.7 (CH2), 31.5
(CH), 27.1 (3CH3), 25.6 (CH2), 21.5 (CH3), 20.8 (CH2), 19.9 (CH2), 19.5 (CH3), 19.3 (C),
16.4 (CH3), 12.5 (CH3), 12.4 (CH3); HRMS (ESI) m/z calcd for C45H62O5SiNa [M+Na]+:
733.4259, found: 733.4251.
combined organic layers were washed with brine, dried over sodium sulfate,
View Article Online
DOI: 10.1039/D0OB00457J
filtered, and concentrated in vacuo. The crude was chromatographed on silica gel
(petroleum ether/EtOAc: 8/1) to give 16 (1.03 g, 90%) as a white foam. [α]D24 -20.3
(c 0.91, CHCl3); IR (cm-1): 3389, 2931, 2856, 2096, 1110, 702; 1H NMR (400 MHz,
CDCl3) δ 7.63-7.71 (m, 4H), 7.31-7.43 (m, 6H), 5.12 (d, J = 5.0 Hz, 1H), 4.23-4.34 (m,
1H), 3.60-3.69 (m, 1H), 3.47-3.58 (m, 1H), 3.25 (dd, J = 12.0, 5.6 Hz, 1H), 3.11 (dd, J
= 12.1, 6.8 Hz, 1H), 2.95 (s, 1H), 2.88 (s, 1H), 2.25-2.34 (m, 1H), 2.03-2.25 (m, 3H),
1.83-2.03 (m, 2H), 1.56-1.81 (m, 6H), 1.25-1.55 (m, 8H), 1.10-1.24 (m, 2H), 1.05 (s,
9H), 0.99 (s, 3H), 0.98 (d, J = 8.0 Hz, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.88 (s, 3H), 0.73-
0.87 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 141.5 (C), 135.9 (2CH), 135.9 (2CH), 134.9
(C), 134.9 (C), 129.6 (CH), 129.5 (CH), 127.6 (2CH), 127.6 (2CH), 121.0 (CH), 75.8
(CH), 73.3 (CH), 72.6 (CH), 59.8 (CH), 57.8 (CH2), 54.5 (CH), 50.0 (CH), 42.9 (C), 42.6
(CH2), 40.1 (CH2), 37.2 (CH2), 36.6 (CH), 36.5 (CH2), 34.0 (CH), 32.0 (CH2), 31.9 (CH2),
31.6 (CH), 30.6 (CH2), 30.1 (CH2), 27.1 (3CH3), 20.8 (CH2), 19.5 (CH3), 19.3 (C), 18.1
(CH3), 14.0 (CH3), 13.1 (CH3); HRMS (ESI) m/z calcd for C43H63N3O3SiNa [M+Na]+:
720.4531, found: 720.4528.
Compound (6)
Compound (7)
To a solution of (COCl)2 (0.10 mL, 1.15 mmol, 8 equiv) and DMSO (0.12 mL, 1.72
mmol, 12 equiv) in dry CH2Cl2 (2 mL) was stirred at -78 °C for 30 min. A solution of
16 (100 mg, 0.14 mmol) in dry CH2Cl2 (4 mL) at -78 °C was added to the solution.
The resulting mixture was stirred at -78 °C for 1 h, then Et3N (0.40 mL, 2.87 mmol,
20 equiv) was added and the mixture was stirred for 30 min. The reaction was
quenched with saturated aqueous NH4Cl and extracted with CH2Cl2 (3×15 mL). The
combined organic layers were washed with water and brine, dried over sodium
sulfate, filtered, and concentrated in vacuo. The crude was chromatographed on
silica gel (petroleum ether/EtOAc: 15/1) to give 6 (73 mg, 73%) as a white foam.
[α]D24 -125.8 (c 0.98, CHCl3); IR (cm-1): 2932, 2097, 1735, 1715, 1110, 702; 1H NMR
(400 MHz, CDCl3) δ 7.64-7.70 (m, 4H), 7.32-7.44 (m, 6H), 5.11 (d, J = 5.1Hz, 1H),
3.49-3.58 (m, 1H), 3.26 (dd, J = 12.0, 5.4 Hz, 1H), 3.12 (dd, J = 12.1, 6.7 Hz, 1H),
2.68-2.80 (m, 1H), 2.53-2.66 (m, 3H), 2.28-2.39 (m, 1H), 2.09-2.23 (m, 1H), 1.94-
2.03 (m, 1H), 1.64-1.92 (m, 6H), 1.39-1.63 (m, 9H), 1.06 (s, 9H), 1.03 (d, J = 6.4 Hz,
3H), 1.01 (s, 3H), 0.99 (d, J = 6.6 Hz, 3H), 0.82-0.94 (m, 2H), 0.77 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 218.3 (C), 213.4 (C), 141.6 (C), 135.9 (2CH), 135.9 (2CH), 134.9
(C), 134.8 (C), 129.6 (CH), 129.6 (CH), 127.6 (2CH), 127.6 (2CH), 120.4 (CH), 73.2
(CH), 66.4 (CH), 57.9 (CH2), 51.4 (CH), 49.7 (CH), 43.5 (CH), 42.5 (CH2), 41.8 (C), 39.7
(CH2), 38.7 (CH2), 37.3 (CH2), 37.0 (CH2), 36.7 (C), 33.1 (CH), 31.9 (CH2), 31.8 (CH2),
31.0 (CH), 27.7 (CH2), 27.1 (3CH3), 20.6 (CH2), 19.6 (CH3), 19.3 (C), 17.7 (CH3), 15.6
(CH3), 13.1 (CH3); HRMS (DART) m/z calcd for C43H60N3O3Si [M+H]+: 694.4398,
found: 694.4386.
To a solution of 13 (3.60 g, 5.06 mmol) in MeOH (80 mL) was added K2CO3 (7.00 g,
50.7 mmol, 10 equiv). The resulting mixture was stirred at 50 °C for 5 h and its pH
value was adjusted to 2 with HCl aqueous solution. The mixture was extracted with
EtOAc (3×60 mL). The combined organic layers were washed with brine, dried over
sodium sulfate, filtered, and concentrated in vacuo. A mixture of the crude and
LiAlH4 (577 mg, 15.2 mmol, 3 equiv) in dry THF (60 mL) was stirred at room
temperature overnight. The mixture was quenched with water slowly and filtered.
The filtrate was extracted with EtOAc (3×60 mL). The combined organic layers were
washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo.
The crude was chromatographed on silica gel (petroleum ether/EtOAc: 1/3) to give
7 (3.13 g, 92%) as a white foam. [α]D -29.0 (c 0.83, CHCl3); IR (cm-1): 3361, 2933,
26
2857, 1110, 701, 509; 1H NMR (400 MHz, CDCl3) δ 7.63-7.71 (m, 4H), 7.32-7.44 (m,
6H), 5.12 (d, J = 5.0 Hz, 1H), 4.29 (td, J = 7.6, 4.8 Hz, 1H), 3.61-3.68 (m, 1H), 3.38-
3.57 (m, 3H), 2.91 (s, br, 2H), 2.28-2.40 (m, 1H), 2.03-2.23 (m, 3H), 1.85-2.02 (m,
2H), 1.78 (s, 1H), 1.52-1.73 (m, 6H), 1.24-1.51 (m, 6H), 1.10-1.24 (m, 2H), 1.05 (s,
9H), 1.00-1.03 (m, 1H), 0.98 (s, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.92 (d, J = 5.9 Hz, 3H),
0.88 (s, 3H), 0.73-0.86 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 141.5 (C), 135.9 (2CH),
135.9 (2CH), 135.0 (C), 134.9 (C), 129.6 (CH), 129.6 (CH), 127.6 (2CH), 127.6 (2CH),
121.0 (CH), 76.1 (CH), 73.4 (CH), 72.6 (CH), 67.8 (CH2), 59.9 (CH), 54.6 (CH), 50.1
(CH), 42.9 (C), 42.6 (CH2), 40.2 (CH2), 37.3 (CH2), 36.6 (CH), 36.5 (CH2), 36.0 (CH),
32.0 (CH2), 31.9 (CH2), 31.6 (CH), 30.0 (CH2), 29.6 (CH2), 27.2 (3CH3), 20.9 (CH2),
19.5 (CH3), 19.3 (C), 17.2 (CH3), 14.1 (CH3), 13.1 (CH3); HRMS (DART) m/z calcd for
C45H65O4Si [M+H]+: 673.4647, found: 673.4633.
Compound (17)
a) To a solution of 6 (50 mg, 0.07 mmol) in MeOH (2 mL) and THF (1 mL) were
added NiCl2·6H2O (3.0 mg, 0.01 mmol, 0.2 equiv) and NaBH4 (22 mg, 0.6 mmol, 8
equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 2.5 h, and was quenched
with water and extracted with EtOAc (3×15 mL). The combined organic layers were
washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo.
The crude was chromatographed on silica gel (petroleum ether/EtOAc: 6/1) to give
17 (36 mg, 79%) as a white foam. b) To a solution of 6 (110 mg, 0.16 mmol) in
MeOH (6 mL) and EtOAc (2 mL) was added Raney-Ni (220 mg). The resulting
mixture was stirred under H2 at 40 °C for 4 h and was filtered. The filtrate was
concentrated in vacuo. The crude was chromatographed on silica gel (petroleum
Compound (16)
To a solution of 7 (1.10 g, 1.63 mmol) and DMAP (20 mg, 0.16 mmol, 0.1 equiv) in
dry CH2Cl2 (20 mL) were added Et3N (0.91 mL, 6.54 mmol, 4 equiv) and TsCl (623
mg, 3.27 mmol, 2 equiv) successively. The resulting mixture was stirred at room
temperature overnight, and was quenched with water and extracted with CH2Cl2
(3×30 mL). The combined organic layers were washed with brine, dried over
sodium sulfate, filtered, and concentrated in vacuo. A mixture of the crude product
and NaN3 (318 g, 4.90 mmol, 3 equiv) in dry DMF (10 mL) was stirred at 60 °C for 6
h. The mixture was quenched with water and extracted with EtOAc (3×30 mL). The
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ether/EtOAc: 6/1) to give 17 (65 mg, 64%) as a white foam. [α]D22 −15.1 (c 0.45,
DCM); IR (film): 3070, 2929, 2856, 1472, 1427, 1261, 1110, 1087 cm−1; 1H NMR (400
MHz, CDCl3) δ 7.64-7.71 (m, 4H), 7.32-7.44 (m, 6H), 5.12 (d, J = 5.0 Hz, 1H), 3.47-
3.58 (m, 1H), 2.83 (dd, J = 10.7, 3.8 Hz, 1H), 2.50-2.67 (m, 1H), 2.28-2.38 (m, 1H),
2.08-2.18 (m, 1H), 1.85-1.95 (m, 1H), 1.62-1.75 (m, 6H), 1.48-1.62 (m, 6H), 1.29-
1.48 (m, 5H), 1.10-1.29 (m, 2H), 1.05 (s, 9H), 1.00-1.09 (m, 3H), 0.99 (s, 3H), 0.90
(d, J = 6.6 Hz, 3H), 0.82 (d, J = 8.6 Hz, 3H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
141.5 (C), 135.9 (2CH), 135.9 (2CH), 135.0 (C), 135.0 (C), 129.6 (CH), 129.6 (CH),
127.6 (2CH), 127.6 (2CH), 121.2 (CH), 74.8 (CH), 73.4 (CH), 69.2 (CH), 63.2 (CH),
60.4 (CH2), 57.8 (CH), 50.3 (CH), 42.7 (CH2), 40.4 (CH2), 40.1 (C), 37.4 (CH2), 36.8
(CH), 33.6 (CH2), 32.2 (CH2), 32.1 (CH2), 31.8 (CH2), 31.5 (CH), 31.3 (CH2), 31.1 (CH),
29.5 (CH2), 27.2 (3CH3), 21.1 (CH2), 19.7 (CH3), 19.6 (CH3), 19.3(C), 18.4 (CH3), 17.0
(CH3); HRMS (ESI-TOF) m/z calcd for C43H61NSi [M+H]+: 636.4595, found: 636.4593.
(-)-Solanidine (1)
2.27-2.37 (m, 1H), 2.10-2.19 (m, 1H), 1.99-2.09 (m, 1H), 1.87-1.99 (m, 2H), 1.84 (s,
View Article Online
DOI: 10.1039/D0OB00457J
1H), 1.63-1.79 (m, 6H), 1.51-1.63 (m, 5H), 1.38-1.50 (m, 3H), 1.19-1.37 (m, 3H),
1.09-1.16 (m, 1H), 1.05 (s, 9H), 1.02 (d, J = 6.9 Hz, 3H), 1.00 (s, 3H), 0.96 (d, J = 6.7
Hz, 3H), 0.80-0.90 (m, 3H), 0.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.5 (C), 135.9
(2CH), 135.9 (2CH), 135.0 (C), 134.9 (C), 129.6 (CH), 129.6 (CH), 127.6 (2CH), 127.6
(2CH), 120.9 (CH), 110.4 (C), 81.6 (CH), 73.3 (CH), 62.8 (CH), 57.9 (CH2), 56.6 (CH),
50.1 (CH), 42.6 (CH2), 40.8 (C), 40.0 (CH), 39.8 (CH2), 37.3 (CH2), 36.8 (C), 36.4 (CH2),
34.0 (CH), 32.2 (CH2), 32.0 (CH2), 32.0 (CH2), 31.5 (CH), 28.1 (CH2), 27.2 (3CH3), 20.9
(CH2), 19.6 (CH3), 19.3 (C), 17.7 (CH3), 16.4 (CH3), 15.7 (CH3); HRMS (DART) m/z [M-
25
H]- calcd for C43H60N3O3Si [M-H]-: 694.4409, found: 694.4410. 22-epi-16: [α]D
-
39.4 (c 1.58, CHCl3); IR (cm-1): 3323, 2933, 2096, 1110, 702, 512; 1H NMR (400 MHz,
CDCl3) δ 7.64-7.70 (m, 4H), 7.32-7.44 (m, 6H), 5.12 (d, J = 4.9 Hz, 1H), 4.32 (td, J =
7.6, 4.6 Hz, 1H), 3.59-3.64 (m, 1H), 3.47-3.57 (m, 1H), 3.07-3.27 (m, 2H), 2.10-2.39
(m, 4H), 1.93 (s, 1H), 1.90 (s, 1H), 1.56-1.80 (m, 5H), 1.30-1.55 (m, 8H), 1.12-1.30
(m, 3H), 1.05 (s, 9H), 0.93-1.00 (m, 1H), 0.98 (d, J = 7.5 Hz, 3H), 0.98 (s, 3H), 0.95
(d, J = 6.5 Hz, 3H), 0.90 (s, 3H) 0.78-0.88 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 141.5
(C), 135.9 (2CH), 135.9 (2CH), 135.0 (C), 134.9 (C), 129.6 (CH), 129.5 (CH), 127.6
(2CH), 127.6 (2CH), 121.0 (CH), 73.3 (CH), 72.1 (CH), 57.9 (CH), 57.3 (CH2), 54.8 (CH),
50.2 (CH), 42.6 (C), 42.6 (CH2), 40.1 (CH2), 37.3 (CH2), 36.6 (CH2), 36.2 (CH), 35.1
(CH), 33.7 (CH), 32.0 (CH2), 31.9 (CH2), 31.6 (CH), 31.4 (CH2), 29.6 (CH2), 27.2 (3CH3),
20.8 (CH2), 19.5 (CH3), 19.3 (C), 17.8 (CH3), 16.3 (CH3), 13.1 (CH3); HRMS (DART) m/z
calcd for C43H64N3O3Si [M+H]+: 698.4711, found: 698.4709.
To a solution of 17 (80 mg, 0.13 mmol) in THF (4 ML) was added TBAF (1.0 M, 1.89
mL, 1.89 mmol, 15 equiv) at 50 °C for 2 h. The reaction was quenched with water
and extracted with EtOAc (3×10 mL). The combined organic layers were washed
with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The
crude was chromatographed on silica gel (petroleum ether/EtOAc: 1/1) to give 1
22
(50 mg, 99%) as a white solid; 208-210 °C; [α]D -20.8 (c 0.50, CH2Cl2); IR (cm-1):
3246, 2927, 1453, 1372, 1053, 1009; 1H NMR (400 MHz, CDCl3) δ 5.35 (d, J = 5.1
Hz, 1H), 3.46-3.57 (m, 1H), 2.81-2.91 (m, 1H), 2.57-2.68 (m, 1H), 2.15-2.36 (m, 2H),
1.93-2.04 (m, 1H), 1.80-1.90 (m, 2H), 1.66-1.80 (m, 4H), 1.40-1.65 (m, 10H), 1.30-
1.39 (m, 1H), 1.25 (s, 1H), 1.05-1.21 (m, 5H), 1.02 (s, 3H), 0.92 (d, J = 6.6 Hz, 3H),
0.84 (s, 3H), 0.83 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 140.9 (C), 121.8
(CH), 74.8 (CH), 71.9 (CH), 69.2 (CH), 63.2 (CH), 60.4 (CH2), 57.8 (CH), 50.4 (CH),
(-)-Tomatidenol (2).
To a solution of 18 (100 mg, 0.14 mmol) in dry CH3CN (4 mL) were added NaI (65
mg, 0.43 mmol, 3 equiv) and TMSCl (91 µL, 0.72 mmol, 5 equiv) at room
temperature. The resulting mixture was stirred at room temperature for 4 h. The
42.5 (CH2), 40.4 (C), 40.1 (CH2), 37.4 (CH2), 36.8 (CH), 36.8 (C), 33.5 (CH2), 32.2 (CH2), reaction was quenched with saturated aqueous Na2S2O3 and extracted with CH2Cl2
31.8 (CH), 31.5 (CH2), 31.2 (CH), 31.2 (CH2), 29.5 (CH2), 21.1 (CH2), 19.7 (CH3), 19.6
(CH3), 18.5 (CH3), 17.1 (CH3); HRMS (ESI-TOF) m/z calcd for C27H43NO [M+H]+:
398.3417, found: 398.3416.
(3×10 mL). The combined organic layers were washed with water and brine, dried
over sodium sulfate, filtered, and concentrated in vacuo. The crude was dissolved
in THF (4 mL) was added a 1.0 mol/L TBAF solution in THF (0.72 mL, 0.72 mmol, 5
equiv). The mixture was stirred at 50 °C overnight, and was quenched with water
and extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed
with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The
residue was chromatographed on silica gel (petroleum ether/EtOAc: 1/1) to give 2
(45 mg, 75%) as a white solid. mp. 215–217 °C; [α]D25 -35.4 (c 0.75, CHCl3) IR (cm-
1): 3314, 2927, 2856, 1462, 1450, 1068, 758; 1H NMR (400 MHz, CDCl3) δ 5.35 (d, J
= 5.4 Hz, 1H), 4.14 (q, J = 7.4 Hz, 1H), 3.46-3.57 (m, 1H), 2.66-2.76 (m, 2H), 2.20-
2.37 (m, 2H), 1.97-2.09 (m, 2H), 1.79-1.89 (m, 2H), 1.59-1.79 (m, 10H), 1.40-1.58
(m, 6H), 1.22-1.40 (m, 4H), 1.03 (s, 3H), 0.98 (d, J = 6.7 Hz, 3H), 0.86 (d, J = 6.7 Hz,
3H), 0.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.0 (C), 121.5 (CH), 100.1 (C), 78.6
(CH), 71.9 (CH), 62.0 (CH), 56.2 (CH), 50.4 (CH2), 50.3 (CH), 43.2 (CH), 42.4 (CH2),
40.8 (C), 40.1 (CH2), 37.4 (CH2), 36.8 (C), 32.9 (CH2), 32.3 (CH2), 31.8 (CH2), 31.5 (CH),
31.2 (CH), 28.7 (CH2), 26.8 (CH2), 21.0 (CH2), 19.6 (CH3), 19.5 (CH3), 16.9 (CH3), 16.1
(CH3); HRMS (DART) m/z calcd for C27H44NO2 [M+H]+: 414.3367, found: 414.3367.
Compound (18) and Compound (22-epi-16).
To a solution of 6 (300 mg, 0.43 mmol) in THF (4 mL) and MeOH (4 mL) was added
NaBH4 (25 mg, 0.65 mmol, 1.5 equiv) at room temperature. The resulting mixture
was stirred for 1 h, and was quenched with water and extracted with EtOAc (3×15
mL). The combined organic layers were washed with brine, dried over sodium
sulfate, filtered, and concentrated in vacuo. The crude was chromatographed on
silica gel (petroleum ether/EtOAc: 10/1-6/1) to give 18 (183 mg, 61%) as a white
foam and 22-epi-16, 67 mg, 22%) as a white foam. To a solution of (COCl)2 (65 µL,
0.77 mmol, 8 equiv) and DMSO (82 µL, 1.15 mmol, 12 equiv) in dry CH2Cl2 (2 mL)
was stirred at -78 °C for 30 min. A solution of 22-epi-16 (67 mg, 0.10 mmol) in dry
CH2Cl2 (4 mL) at -78 °C was added to the solution. The resulting mixture was stirred
at -78 °C for 1 h, then Et3N (0.27 mL, 1.92 mmol, 20 equiv) was added and the
mixture was stirred for 30 min. The reaction was quenched with saturated aqueous
NH4Cl and extracted with CH2Cl2 (3×10 mL). The combined organic layers were
washed with water and brine, dried over sodium sulfate, filtered, and concentrated
in vacuo. The crude was chromatographed on silica gel (petroleum ether/EtOAc:
15/1) to give 6 (50 mg, 75%) as a white foam 18: [α]D24 -38.4 (c 0.72, CHCl3); IR
(cm-1): 3436, 2932, 2902, 2096, 1110 702, 510; 1H NMR (400 MHz, CDCl3) δ 7.63-
7.71 (m, 4H), 7.32-7.44 (m, 6H), 5.11 (d, J = 5.1 Hz, 1H), 4.57 (q, J = 7.6 Hz, 1H),
3.47-3.57 (m, 1H), 3.22 (dd, J = 12.0, 5.9 Hz, 1H), 3.13 (dd, J = 12.0, 6.8 Hz, 1H),
Conclusions
In summary, we have achieved the formal asymmetric synthesis of
(-)-solanidine (1) in 12 steps with 32% overall yield and (-)-
tomatidenol (2) in 13 steps with 18.7% overall yieldby employing the
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
(R)
intact skeleton of (-)-diosgenin (5). The synthetic strategy described
herein is concise and could also be used for the synthesis of 25-
configuration solanidine and tomatidenol-related steroidal alkaloids,
as well as analogues from steroidal sapogenins. The synthesis of
other tomatidenol congeners, in particular (+)-tomatidine along this
line, are now under investigation in our laboratory, and will be
reported in due course.
View Article Online
DOI: 10.1039/D0OB00457J
HN
H
(R)
O
H
H
H
AcO
H
Solasodine acetate (69%)
O
H
TMSCl, NaI
(S)
N3
H
H
(S)
AcO
N
H
O
H
Conflicts of interest
H
H
There are no conflicts to declare.
AcO
Tomatidenol acetate (8%)
(by-product)
Acknowledgements
We thank Prof. Jing-Han Gui and Dr. Jing-jing Wu (Shanghai
Institute of Organic Chemistry) for helpful discussions.
15 (a) L. L. Hou, Y. Shi, Z. D. Zhang, J. J. Wu, Q. X. Yang, W. S. Tian,
J. Org. Chem. 2017, 82, 7463-7469. (b) J. J. Wu, R. Gao, Y. Shi,
W. S. Tian, Tetrahedron Lett. 2015, 56, 6639-6642. (c) J. J. Wu,
Y. Shi, W. S. Tian, Chem. Commun. 2016, 52, 1942-1944. (d) X.
F. Zhang, J. J. Wu, Y. Shi, J. R. Lin, W. S. Tian, Tetrahedron Lett.
2014, 55, 4639-4642. (e) X. M. Tang, Q. H. Xu, J. Wang, J. R.
Lin, R. H. Jin, W. S. Tian, Acta Chim. Sin. 2007, 65, 2315-2319.
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X. Xu, H. D. Miao, X. S. Yao, Z. Yang, J. Org. Chem. 2003, 68,
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6945-6948.
Notes and references
1
2
3
S. F. Osman, S. L. Sinden, Phytochemistry 1982, 21, 2763-2764.
P. Gregory, Am. Potato J. 1984, 61, 115-122.
(a) M. Z. Stankovic, N. C. Nikolic, R. Palic, M. D. Cakic, V. B.
Veljkovic, Potato Res. 1994, 37, 271-278. (b) N. C. Nikolic, M.
Z. Stankovic, D. Z. Markovic, Med. Sci. Monit. 2005, 11, 200-
205. (c) J. Attoumbre, P. Giordanengo, S. Baltora-Rosset, J.
Sep. Sci. 2013, 36, 2379-2385.
4
5
6
(a) A. Petelot, du Laos et du Viet-Nam, 1954, 4, 201. (b) K.
Stopp, (Ed.: K. Schreiber), 1961, pp. 255. (c) S. K. Jain, S. K.
Borthakur, (Ed.: W.G. D’ Arcy), Columbia University Press,
New York, 1986, pp. 577. (d) Le T. Quyen, N. H. Khoi, N. N.
Suong, K. Schreiber, H. Ripperger, Planta Med. 1987, 53, 292-
293.
(a) P. M. Boll, Acta Chem. Scand. 1962, 16, 1819-1830. (b) H.
Sander, M. Alkeymeyer, R. Hänsel, Arch. Pharm. 1962, 295, 6-
12. (c) K. Schreiber, H. Roensch, Abhandl. Deut. Akad. Wiss.
Berlin, Kl. Chem., Geol. Biol. 1963, 4, 395-407. (d) K. Schreiber,
H. Roensch, Tetrahedron Lett. 1963, 4, 329-334. (e) S. Makleit,
R. Bognar, Acta Chim. Acad. Sci. Hung. 1963, 38, 53-54.
(a) S. Aoki, Y. Watanabe, M. Sanagawa, A. Setiawan, N. Kotoku,
M. Kobayashi, J. Am. Chem. Soc. 2006, 128, 3148-3149. (b) Y.
Watanabe, S. Aoki, D. Tanabe, A. Setiawan, M. Kobayashi,
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7
8
9
B. Wolters, Planta Med 1966, 14, 392-401.
Do Tat Loi, Scientific and Technical Press, Hanoi, 1977, pp. 273.
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13 Z. D. Zhang, Y. Shi, J. J. Wu, J. R. Lin, W. S. Tian, Org. Lett. 2016,
18, 3038-3040.
14 In our previous synthesis of (-)-solanidine, only 8% (-)-
tomatidenol acetate was separated as by-product. See J. J. Wu,
Y. Shi, W. S. Tian, Tetrahedron Lett. 2015, 56, 1215-1217.
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DOI: 10.1039/D0OB00457J
Table of Contents Entry
H
H
(R)
(S)
N
H
(R)
H
H
O
(R)
HO
Two stereoselective
1
(-)-Solanidine ( )
O
cascade transformations
H
(S)
H
H
(S)
HO
N
5
(-)-Diosgenin ( )
H
O
H
H
H
HO
2
(-)-Tomatidenol ( )
The asymmetric synthesis of (-)-solanidine (1) and (-)-tomatidenol (2) has been achieved by employing
two cascade reactions including a modified cascade ring-switching reaction of furstan-26-acid and a
cascade azide reduction/intramolecular reductive amination as key transformations. This synthesis of
(-)-solanidine (1) and (-)-tomatidenol (2) was completed in 12 steps with 32% overall yield and 13 steps
with 18.7% overall yield, respectively.