Divergent Synthesis of Solanidine and 22-epi-Solanidine

Article abstract of DOI:10.1021/acs.joc.7b01133

A divergent synthesis of solanidine and 22-epi-solanidine, two 25S natural steroidal alkaloids, from 25R-configured diosgenin acetate, is described. Initially, solanidine was synthesized through a series of transformations including a cascade ring-switching process of furostan-26-acid, an epimerization of C25 controlled by the conformation of six-membered lactone ring, an intramolecular Schmidt reaction, and an imine reduction/intramolecular aminolysis process. To address the epimerization issue during Schmidt reaction, an improved synthesis was developed, which also led to a synthesis of 22-epi-solanidine. In this synthesis, selective transformation of azido lactone to azido diol and amino diol was realized through a reduction relay tactic. The azido diol was transformed to solanidine via an intramolecular Schmidt reaction/N-alkylation/reduction process and to 22-epi-solanidine via an intramolecular double N-alkylation process.

Full text of DOI:10.1021/acs.joc.7b01133

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Article
Divergent Synthesis of Solanidine and 22-epi-Solanidine
Ling-Li Hou, Yong Shi, Zhi-Dan Zhang, Jing-Jing Wu, Qing-Xiong Yang, and Wei-Sheng Tian
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 16 Jun 2017
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Divergent Synthesis of Solanidine and 22-epi-Solanidine
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Ling-Li Hou,‡ Yong Shi,*,† Zhi-Dan Zhang,† Jing-Jing Wu,† Qing-Xiong Yang,‡ and Wei-Sheng Tian*,†
† CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
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‡
School of Chemistry & Materials Science, Guizhou Normal University, 116 Baoshan North Road,
Guiyang 550001, Guizhou, China
Email: shiong81@sioc.ac.cn (Y. Shi); wstian@sioc.ac.cn (W.-S. Tian)
Schmidt rxn
N-alkylation
ring-switching process
imine reduction
H
O
O
H
(R)
H
22
(S) 25
N
H
H
H
H
HO
diosgenin acetate
solanidine (22R)
22-epi-solanidine (22S)
C25 epimerization
reduction relay process
double N-alkylation
Abstract
A divergent synthesis of solanidine and 22-epi-solanidine, two 25S natural steroidal alkaloids, from
25R-configured diosgenin acetate, is described. Initially, solanidine was synthesized through a series
of transformations including a cascade ring-switching process of furostan-26-acid, an epimerization
of C25 controlled by the conformation of six-membered lactone ring, an intramolecular Schmidt
reaction, and an imine reduction/intramolecular aminolysis process. To address the epimerization
issue during Schmidt reaction, an improved synthesis was developed, which also led to a synthesis of
22-epi-solanidine. In this synthesis, selective transformation of azido lactone to azido diol and amino
diol was realized through a reduction relay tactic. The azido diol was transformed to solanidine via an
intramolecular Schmidt reaction/N-alkylation/reduction process and to 22-epi-solanidine via an
intramolecular double N-alkylation process.
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Introduction
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Possessing various bioactivities and structures, steroidal alkaloids have drawn great interest from
researchers.1 Solasodine (2) and solanidine (4) represent two types of cholestane alkaloids isolated
from several potato species, mainly present as glycosides. The former is essentially an analogue of
diosgenin (1), a steroidal sapogenin, and the latter has a different arrangement of rings EF (Figure 1).
Solasodine (2) and tomatidenol (3) are known to act as natural insect deterrents, have antimicrobial
properties, can inhibit acetylcholinesterase, and disrupt cell membranes.2 Solanidine (4) and
demissidine (5) can inhibit proliferation and exhibit obvious antitumor effect.3
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(R)
(R)
O
O
HN(R)
25
F
H
H
22
O
16
E
H
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diosgenin (1)
solasodine (2)
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(S)
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HO
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6
solanidine (4)
tomatidienol (3)
demissidine (5, 5,6-dihydro-4)
H
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(S)
(S)
(S)
N
H
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O
5
H
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H
H
HO
O
6
22-epi-solanidine (6, 22S)
dafachronic acid (7)
Figure 1. Structures of Diosgenin and Biologically Interesting Natural Products
Needing to replace one oxygen atom of the spiroketal with one nitrogen atom, the synthesis of
solasodine (2) from diosgenin (1) has been widely investigated, resulting in ten syntheses.4 However,
fewer syntheses of solanidine (4) and demissidine (5) were reported. As shown in Scheme 1, 4 was
synthesized from tomatidienol (3), a naturally occurring C25S-configured steroidal alkaloid, by
Schreiber and Rönsch through reduction/oxidation manipulations.5 Adam and Schreiber prepared 5
from pregnenolone acetate (8) by addition of 2-lithio-5-methylpyridine followed by
non-stereoselective hydrogenation and Hofmann–Löffler–Freytag cyclization.6 In 2013, Brewer and
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co-workers reported a 12-step synthesis of 5 from epiandrosterone, featuring a ring fragmentation
1,3-dipolar cycloaddition approach.7 The synthesis of 4/5 from the corresponding steroidal sapogenin
requires the replacement of both oxygen atoms of the spiroketal with one nitrogen atom and the
epimerization of C25, which was considered unpractical and therefore less explored. Recently, we
developed a synthesis of 4/5 from steroidal sapogenins, which, although efficient, suffered from
severe epimerization which lowered the overall yield by one third.8 Herein, we report an improved
synthesis of solanidine, which also enabled a synthesis of 22-epi-solanidine (6), the first
solanidine-type alkaloid with C22S configuration discovered from nature.9
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Scheme 1. Reported Syntheses of Solanidine (4)/Demissidine (5)
To synthesize 4/6 from diosgenin (1), we need to replace three C–O bonds (C16–O, C22–O, and C26–
O) with C–N bonds, two of which should proceed stereoselectively, and to epimerize the
configuration of C25. It was reported that the ring F of diosgenin (1) could be opened reductively to
give the C22R-configured furostanol 14,10 based on which we devised our synthetic plan (Scheme 2).
We envisioned that the C26–N bond of solanidine (4) could be constructed via an intramolecular
N-alkylation and C22–N be established through an intramolecular Schmidt reaction of azide 13
followed by a substrate-controlled reduction of the resultant imine 11. Similarly, both C26–N and
C22–N bonds of 22-epi-solanidine (6) could be built via an intramolecular N-alkylation of amine 13.
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Azide/amine 13 could be prepared from 14 via an epimerization of C25 and a nucleophilic
5
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substitution after opening ring E through C16 iodination.
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Results and Discussion
Scheme 2. a) Synthetic Plan of Solanidine (4) and 22-epi-Solanidine (6); b) Ring-switcing Process and
Epimerization of C25.
As depicted in Scheme 2, our synthesis began with the preparation of furostan-26-acid 16 from
diosgenin acetate (15) through a BF3•Et2O/Et3SiH reduction-Jones oxidation process. We then
developed a ring-switching process to open the ring E of 16 with the assistance of the C26-acid.
Treatment of acid 16 with BF3•Et2O (12 equiv)/Ac2O (8 equiv) in the presence of Bu4NI (6 equiv)
provided iodide 17 in high yield on multigram scale.11 Considering that using excessive amount of
Bu4NI was not convenient in practice, especially on a large scale, we optimized the ring-opening
process. Finally, treating 16 with trifluoroacetic anhydride/lithium iodide in dichloromethane
(DCM)/MeCN afforded 17 in comparable high yield on multigram scale.12
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With 17 in hand, we first confirmed the stereochemistry of lactone ring and explored the
epimerization of C25. The C16-I bond was reductively cleaved by subjecting 17 to Zn/HOAc in
refluxing DCM to provide 18, which was confirmed to be C22R- and C25R-configured via an X-ray
analysis. Treatment of 18 with K2CO3 in MeOH at 45 °C for 2 h not only removed the C3-acetate, but
also, to our delight, epimerized the C25, providing the 25S-configured lactone 19 in 90% yield as a
single isomer on multigram scale. In 19, both substituents (the steroidal backbone and the C26
methyl group) equatorially lie on chair-conformation lactone ring, thus, the epimerization is
preferred. Lactone 19 is an advanced intermediate in Nishizawa’s synthesis of osladin,13 a plant
sweetening agent, and the spectroscopic properties of the synthetic 19 are consistent with those
reported, which, therefore, constituted a formal synthesis of osladin.11
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Treated with sodium azide in DMF at 65 °C, 17 underwent substitution to deliver azide 20 in 81%
yield. Likewise, epimerization of its C25 configuration from R to S was realized by treating with K2CO3
in MeOH at 45 °C for 2 h and then with 1.2 N HCl, giving 21 in 95% yield (Scheme 3).
It is well-known that esters could serve as leaving groups under acidic conditions. For example,
lactones could be converted to ω-halo acids or esters upon treating with HBr or HCl. This property
might be employed to trigger an intramolecular Schmidt reaction,14 as the C16β azido group was
close to the electrophilic C22. After many attempts, we found that desired Schmidt reaction
proceeded smoothly when 21 was treated with SOCl2 in MeOH (generates in situ a methanolic
solution of HCl) at ambient temperature, delivering imine 24 in good yield, with the exposed C3-OH
not being affected. To our disappointment, the strong acidic condition caused partial epimerization of
C25, and the isolated product was a 2/1 inseparable mixture of 24 and its C25-epimer. Using less
amount of SOCl2, conducting the reaction at lower temperatures, and preparing HCl solution by other
methods did not provide better results. The mixture of inseparable epimers was therefore used in the
next step.
Reduction of imine 24 and its C25-epimer with NaBH4 in ethanol was accompanied with spontaneous
intramolecular aminolysis, which was driven to completion by heating the reaction mixture at reflux,
giving lactam 26 in 41% yield and 25-epi-26 in 16% yield. Further reduction of 26 with sodium
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bis(2-methoxyethoxy)aluminumhydride (Red-Al) in toluene at ambient temperature gave solanidine
(4) in 73% yield. Using the same route, demissidine (5) was also synthesized from tigogenin acetate in
eight steps.8
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Scheme 3. Completion of the synthesis of solanidine (4)
Partial epimerization of the C25 occurred during the course of the SOCl2-activated intramolecular
Schmidt reaction of 21 because it is at the α position of a carbonyl group. Converting the lactone of
21 to a 22,26-diol would solve this problem, thus, we altered our synthesis accordingly. As depicted in
Scheme 2a, transforming both hydroxyl groups of azido diol 13 (X = N3, R = H) to mesylates would
allow us to perform a similar intramolecular Schimdt reaction to form an imine (like 24), which could
undergo N-alkylation again and the generated imine salt be reduced to give solanidine 4. On the
other hand, reducing both azide and lactone to amino diol 13 (X = NH2, R = H) and performing
N-alkylation twice would deliver 22-epi-solanidine 6.
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Scheme 4. Divergent Preparation of 29 and 30 Through a Reduction Relay Procedure.
As azides are reactive under reducing conditions and most reagents that could reduce esters also
reduce azides, the first challenge of our plan was to convert lactone to diol in the presence of azido
group. One advantage we could take is that the C16-azide is a sterically hindered one;
chemoselective reduction might be achieved at low temperature. The C3-OH of 21 was protected as
TBDPS ether to give 27 in quantitative yield (70% from 17 over 3 steps, Scheme 4). Treatment of 27
with diisobutylaluminium hydride (DIBAL-H) in dichloromethane at –70 °C gave a complex mixture.
Reduction of 27 with LiAlH4 at 0 °C also gave a mixture of 29, 30, and azido hemiacetal 28. To our
delight, at –70 °C, this reaction gave only 29 and 28, which, we reasoned, could lead to 29 upon
further reduction of the crude with NaBH4. We therefore reduced 27 with LiAlH4 at –70 °C, quenched
the reaction with MeOH, and added NaBH4 to the mixture to convert 28 to 29 completely. This
reduction relay procedure provided the azido diol 29 in one flask with an 86% yield.
Preparation of amino diol 30, which, we thought at first, could be realized via performing the LiAlH4
reduction of 27 at room temperature, was somewhat problematic. The reduction could not be driven
to completion at ambient temperature with excess of LiAlH4 or DIBAL-H. At elevated temperatures, a
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complex mixture was obtained. Considering NiCl2•6H2O/NaBH4 could also convert azides to amines,15
we added NiCl2•6H2O (0.20 equiv) to the previous reduction system and obtained 30 in 74% yield
from 27.
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With both 29 and 30 in hand, we tried to convert them to 4 and 6, respectively. As shown in Scheme
5, treatment of 29 with MsCl (8 equiv) gave bismesylate 31, which, without purification, was heated
at reflux in MeCN to promote the intramolecular Schmidt reaction and the N-alkylation. The reaction
proceeded smoothly and the newly-formed imine salt was treated with NaBH4 in MeOH to set the
correct C22 configuration under the control of substrate, delivering the protected solanidine 35 in 54%
yield. Removal of the TBDPS group of 35 with TBAF afforded solanidine (4), the analytical data of
which matched with those reported.8 In practice, the process of converting 29 to 35 could be carried
out in one flask without purification.
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Scheme 5. An Improved Synthesis of Solanidine.
We then turned to synthesize 22-epi-solanidine (6) from the amino diol 30, which was found difficult
to realize (Scheme 6). Selective transformation of C26-OH to 4-methylbenzenesulfonate or of both
C22- and C26-OHs in the presence of C16-NH2 to sulfonates (Ms or Ts) were unsuccessful. Other
conditions that reportedly could transform amino alcohols to cyclic amines (e.g. PPh3/DEAD;16
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PPh3/Br2;17 or SOCl218) also did not work.
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Failing to synthesize 6 from 30, we revisited our plan and considered the azido diol 29 more suitable
for our purpose because it did not need selective transformations. We therefore treated 29 with
MsCl in pyridine/DCM and the crude azide 31 with NaBH4/NiCl2•6H2O in ether/MeOH, and found that
the resultant 38 underwent the wanted double N-alkylation spontaneously, delivering 37 in 38% yield,
along with 35 in 10% yield.19 Removal of the TBDPS with TBAF gave 22-epi-solanidine (6), the
analytical data of which matched with those reported.9
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Scheme 6. Completion of the Synthesis of 22-epi-Solanidine 6.
Conclusion
In summary, we developed an efficient synthesis of solanidine (4) from diosgenin acetate, featuring a
cascade ring-switching process of the furostan-26-acid 16, a SOCl2/MeOH-promoted intramolecular
Schmidt reaction of the azido lactone 21, and a substrate-controlled, stereoselective
reduction/intramolecular aminolysis. This synthetic route minimized the use of protecting groups,
but suffered from severe epimerization in the course of Schmidt reaction.
We then developed an improved route leading to both solanidine 4 (24% overall yield) and
22-epi-solanidine 6 (17% overall yield). Selective transformation of the azido lactone 27 to the azido
diol 29 and the amino diol 30 was realized via stepwise reduction. Diol 29 was transformed to
solanidine (4) through an intramolecular Schmidt reaction/N-alkylation/reduction process and to
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22-epi-solanidine (6) through an intramolecular double N-alkylation, respectively. The strategy and
chemistry described herein could also be employed to synthesize other 25S-configured steroidal
natural products, such as dafachronic acid A and tomatine-related steroidal alkaloids, from steroidal
sapogenins.
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Experimental Section
General Methods: All reactions sensitive to air or moisture were performed in flame-dried round
bottom flasks with rubber septum under a positive pressure of argon or nitrogen atmosphere, unless
otherwise noted. Air and moisture-sensitive liquids and solutions were transferred via syringe and
stainless steel cannula. Tetrahydrofuran (THF) was distilled from sodium/benzophenone, methylene
chloride from calcium hydride, N,N-dimethylformamide (DMF) from calcium hydride under reduced
pressure, others according to the standard procedures described in Purification of Laboratory
Chemicals. 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), DMSO-d6 (2.50), pyridine-d5
(8.74); 13C NMR: CDCl3 (77.16), DMSO-d6 (39.52), pyridine-d5 (150.35)]. The following abbreviations
were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, br = broad.
16α-Iodo lactone 17:11 Method 1. To a stirred solution of furostan-26-acid 16 (crude product
prepared from diosgenin acetate (15.16 g, 33 mmol) through reduction and Jones oxidation8) and LiI
(13.15 g, 99 mmol, 3 equiv) in DCM/MeCN (200 mL/50 mL, freshly distilled) at 0 °C was added
trifluoroacetic anhydride (9.30 mL, 66 mmol, 2 equiv) slowly. The resulting mixture was stirred for 1 h
at ambient temperature and TLC indicated that 16 was completely consumed. The reaction was
quenched with saturated aqueous NaHCO3/ NaSO3 solution, and extracted with DCM (3×70 mL). The
combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced
pressure, and purified via flash column chromatography on silica gel (PE/EA: 8/1 to 3/1) to deliver 17
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(14.40 g, 75% from 15) as a white solid. Method 2. To a stirred solution of acid 16 (945 mg, 2 mmol)
in DCM (20 mL, freshly distilled) at 0 °C was added a solution of Bu4NI (4.46 g, 12 mmol, 6 equiv) in
DCM (5 mL) solution, BF3•Et2O (1.6 mL, 16 mmol, 8 equiv, dropwise), and Ac2O (1.6 mL, 16 mmol, 8
equiv), sequentially. The reaction mixture was stirred for 7 h at 0 °C and TLC indicated that acid 16
was completely consumed. Quenched with saturated aqueous NaHCO3 solution, extracted with DCM
(3×50 mL), combined organic layer was dried over Na2SO4 and concentrated in vacuo. Purification via
flash column chromatography on silica gel (PE/EA: 10/1–6/1–2/1–1/1) delivered lactone 17 (916 mg,
92%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.38 (s, 1H), 4.73 (d, J = 11.5 Hz, 1H), 4.61 (dt, J =
10.4, 5.3 Hz, 1H), 4.11-4.08 (m, 1H), 2.68 (q, J = 7.4 Hz, 1H), 2.34 – 2.30 (m, 2H), 2.04 (s, 3H), 1.24 (d, J
= 6.8 Hz, 3H), 1.01 (s, 3H), 0.96 (d, J = 6.7 Hz, 3H), 0.72 (s, 3H).
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Lactone 18:11 Iodo lactone 17 was treated with activated zinc powder (488 mg, 7.5 mmol, 15 equiv)
in HOAc (10 mL) at ambient temperature for 10 h. The reaction was quenched with saturated
NaHCO3 and extracted with DCM for three times. The combined organic layers were dried over
Na2SO4, concentrated under reduced pressure and purified through flash column chromatography on
1
silica gel (PE/EA: 10/1–8/1–6/1) to produce lactone 18 (228 mg, 99%) as a white solid. H NMR (400
MHz, CDCl3) δ 5.37 (1H, d, J = 4.6 Hz), 4.63-4.57 (1H, m), 4.34 (1H, dt, J = 8.8, 4.1 Hz), 2.61 (1H, dq, J =
14.5, 6.9 Hz), 2.33-2.31 (2H, m), 2.03 (3H, s), 1.22 (3H, d, J = 6.8 Hz), 1.02 (3H, s), 0.98 (3H, d, J = 6.7
Hz), 0.71 (3H, s).
25S-Lactone 19:11 Lactone 18 (128 mg, 0.28 mmol) was treated with K2CO3 (386 mg, 2.8 mmol, 10
equiv) in MeOH (5 mL) at 45 ºC for 2 h. The reaction mixture was then acidified with diluted HCl
aqueous solution at ambient temperature, and stirred for 2 h. The mixture was diluted with water
and extracted with CHCl3 (3×20 mL). The combined organic layers were washed with brine, dried over
Na2SO4, concentrated, and purified through flash column chromatography on silica gel (PE/EA: 6/1–
4/1–3/1) to afford lactone 19 (105 mg, 90%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.35 (1H, d,
J = 5.1 Hz), 4.38 (1H, dt, J = 11.6, 3.3 Hz), 3.56-3.48 (1H, m), 2.42-2.36 (1H, m), 1.29 (3H, d, J = 7.0 Hz),
1.01 (3H, s), 0.95 (3H, d, J = 6.7 Hz), 0.71 (s, 3H).
Azido lactone 20:8 A solution of iodide 17 (10.01 g, 17.2 mmol) in dry DMF (75 mL) was treated with
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NaN3 (3.36 g, 51.6 mmol, 3 equiv) at 65 °C for 15 h. The mixture was quenched with water (300 mL)
and extracted with EtOAc (200 mL×4). The combined organic layers were washed with saturated
aqueous LiCl solution (100 mL×2) and brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The crude 20 was used in the next step without purification. A 1.50 g (3.1 mmol)
scale reaction was performed to give 20 (1.50 g) in 81% yield. 1H NMR (400 MHz, CDCl3) δ 5.37 (d, J =
4.7 Hz, 1H), 4.60 (dt, J = 15.7, 7.2 Hz, 1H), 4.55 – 4.47 (m, 1H), 4.05 (td, J = 8.3, 5.3 Hz, 1H), 2.72 –
2.59 (m, 1H), 2.04 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H), 1.03 (s, 3H), 1.00 (d, J = 6.8 Hz, 3H), 0.85 (s, 3H).
25S-Azido lactone 21:8 A solution of the crude 20 and K2CO3 (23.74 mg, 172 mmol, 10 equiv) in
MeOH (170 mL) was heated to react at 45 ºC for 3 h. Diluted HCl aqueous solution (4.8 M, 200 mL)
was added when TLC showed that the starting material was fully consumed, and the reaction was
stirred for another 4 h at ambient temperature. The mixture was extracted with CHCl2 (2×150 mL).
The combined organic layers were washed with brine, dried over Na2SO4, concentrated to dryness,
and used in the next step without purification. A 500 mg (0.86 mmol) scale reaction was performed
to give 21 (406 mg) in 95% yield. 1H NMR (400 MHz, CDCl3) δ 5.34 (d, J = 4.9 Hz, 1H), 4.56 (dt, J = 11.4,
3.4 Hz, 1H), 4.03 (dd, J = 8.0, 3.0 Hz, 1H), 3.57 – 3.46 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H), 1.02 (s, 3H),
0.97 (d, J = 6.8 Hz, 3H), 0.85 (s, 3H).
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Imine 24:8 To a solution of 21 (1.35 g, 3.0 mmol) in MeOH (30 mL) was added SOCl2 (5 mL) slowly at
0 °C. The resulting solution was stirred at 0 °C for 10 min and then at ambient temperature for 4 h.
The reaction mixture was quenched with a saturated aqueous NaHCO3 solution and extracted with
DCM (50 mL×4). The combined organic layers were washed with brine, dried over Na2SO4, filtered,
and concentrated under reduced pressure. The crude product was purified via flash column
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chromatography on silica gel (PE/EA: 1/1–0/1) to give 24 (1.0 g, 77%) as a white solid. H NMR (400
MHz, CDCl3) δ 5.34 (d, J = 5.2 Hz, 1H), 4.45 (dd, J = 15.1, 7.0 Hz, 1H), 3.67 (d, J = 4.0 Hz, 4H), 3.51 (dt, J
= 11.0, 5.8 Hz, 1H), 2.67 – 2.59 (m, 1H), 2.51 (dq, J = 14.1, 7.0 Hz, 1H), 1.18 (dd, J = 7.0, 2.5 Hz, 4H),
1.06 (d, J = 7.4 Hz, 4H), 0.99 (s, 3H), 0.53 (s, 3H).
Amide 26:8 To a solution of 24 (350 mg, 0.8 mmol) in EtOH (10 mL) were added NaBH4 (120 mg, 3.2
mmol) at ambient temperature under argon. The mixture was stirred at ambient temperature for two
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hour. Imine 24 disappeared on TLC plate (two sets of products formed) and the mixture was heated
at reflux until the more polar products were completely converted to the less polar ones.
Concentration under reduced pressure and purification of the crude product (PE/EA: 1/1 to EA)
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afforded 26 (134 mg, 41%) as a white solid and 25-epi-26 (53 mg, 16%) as a white solid. 26: H NMR
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(400 MHz, CDCl3) δ 5.34 (d, J = 4.6 Hz, 1H), 3.91 (dd, J = 17.4, 8.3 Hz, 1H), 3.51 (dd, J = 13.0, 8.7 Hz,
1H), 3.09 (t, J = 9.8 Hz, 1H), 2.37 (dt, J = 14.6, 8.1 Hz, 1H), 2.33 – 2.18 (m, 3H), 1.17 (d, J = 7.0 Hz, 3H),
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5.34 (d, J = 3.9 Hz, 1H), 3.98 – 3.85 (m, 1H), 3.51 (d, J = 4.4 Hz, 1H), 3.10 – 3.02 (m, 1H), 2.45 – 2.31
(m, 2H), 2.25 (dd, J = 17.2, 8.0 Hz, 2H), 1.21 (d, J = 7.3 Hz, 3H), 0.99 (d, J = 6.7 Hz, 6H), 0.76 (s, 3H).
Solanidine 4:8 To a solution of amide 26 (50 mg, 0.12 mmol) in toluene (2.0 mL, freshly distilled) was
added Red-Al (60% wt% in toluene, 0.22 mL, 1.2 mmol, 10 equiv) at 0 °C under argon. The ice-water
bath was removed and the mixture was stirred at ambient temperature until TLC showed complete
consumption of 26 (3.5 h). The mixture was quenched with 1 N aqueous NaOH solution and
extracted with chloroform (50 mL×3). The combined organic layers were washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash column
chromatography on silica gel (PE/EA: 1/1 to EA) afforded solanidine 4 (35 mg, 73%) as a white solid.
16β-Azido lactone 27: The crude 21 and imidazole (2.345 g, 34 mmol, 2 equiv) were dissolved in
DCM (90 mL), and TBDPSCl (5.40 mL, 20.6 mmol, 1.2 equiv) was added slowly at 0 °C. The reaction
was stirred at ambient temperature for 1 h, then quenched with a saturated solution of NH4Cl,
diluted with water, and extracted with DCM (100 mL×3). The combined organic layers were washed
with brine, dried over Na2SO4, concentrated under reduced pressure, and purified through flash
column chromatography (PE/EA: 10/1 to 8/1) on silica gel to give 27 (14.40 g, 70% for 3 steps) as a
colorless syrup. Rf = 0.40 (silica gel, PE/EA: 5/1); [α]D22 + 6.0 (c 1.00, DCM); IR (film): 2988, 2015, 1728,
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1461, 1275, 1260, 1084, 764, 749, 704 cm-1; H NMR (400 MHz, CDCl3) δ 7.72 – 7.63 (m, 4H), 7.45 –
7.32 (m, 6H), 5.14 – 5.09 (m, 1H), 4.55 (dt, J = 11.4, 3.5 Hz, 1H), 4.06 – 3.95 (m, 1H), 3.57 – 3.47 (m,
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1H), 1.31 (d, J = 7.1 Hz, 3H), 1.06 (s, 9H), 0.99 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.82 (s, 3H); C NMR
(100 MHz, CDCl3) δ 174.6 (C), 141.5 (C), 135.7 (2CH), 135.7 (2CH), 134.7 (C), 134.7 (C), 129.4 (CH),
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129.4 (CH), 127.4 (2CH), 127.4 (2CH), 120.4 (CH), 83.0 (CH), 73.1 (CH), 61.3 (CH), 55.1 (CH), 54.7 (CH),
49.8 (CH), 42.9 (C), 42.4 (CH2), 39.6 (CH2), 37.1 (CH2), 36.4 (CH), 35.1 (CH), 32.8 (CH2), 31.8 (CH2), 31.6
(CH2), 31.4 (CH), 28.5 (CH2), 27.0 (3CH3) , 23.0 (CH2), 20.5 (CH2), 19.4 (CH3), 19.1 (C), 17.3 (CH3), 12.6
(CH3), 12.2 (CH3); MS-ESI (m/z): 732.3 [M+K]+; HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C43H59O3N3Si:
716.4218, found: 716.4215.
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Azido diol 29: At − 70 °C, a solution of lactone 27 (693 mg, 1.0 mmol) in THF (10 mL) was treated with
LiAlH4 (133 mg, 3.5 mmol, 3.5 equiv) for 1.5 h. TLC analysis indicated the complete consumption of
the starting material. The reaction was quenched with MeOH at −70 °C and treated with NaBH4 (302
mg, 8 mmol, 8 equiv) at 0 °C for 3 h. Then the mixture was quenched with 1.2 N HCl, diluted with
MeOH, concentrated under reduced pressure, and purified through flash column chromatography on
silica gel (PE/EA: 5/2 to 2/1) to give diol 29 (598 mg, 86%) as a colorless syrup. Rf = 0.33 (silica gel,
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PE/EA: 1/1); [α]D (c, DCM); IR (film): 3362, 2933, 2103, 1471, 1462, 1427, 1110 cm-1; H NMR (400
MHz, CDCl3) δ 7.72 – 7.63 (m, 4H), 7.48 – 7.31 (m, 6H), 5.11 (s, 1H), 4.08 – 4.01 (m, 1H), 3.72 (d, J =
10.3 Hz, 1H), 3.55 – 3.40 (m, 3H), 1.05 (s, 9H), 0.99 (s, 3H), 0.95 (d, J = 7.8 Hz, 3H), 0.94 (d, J = 8.0 Hz,
2H), 0.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.4 (C), 135.7 (2CH), 135.7 (2CH), 134.8 (C), 134.7 (C),
129.4 (CH), 129.4 (CH), 127.4 (2CH), 127.4 (2CH), 120.5 (CH), 73.6 (CH), 73.1 (CH), 67.8 (CH2), 62.1
(CH), 56.1 (CH), 54.7 (CH), 49.8 (CH), 42.7 (C), 42.4 (CH2), 39.5 (CH2), 38.1 (CH), 37.1 (CH2), 36.4 (C),
36.0 (CH), 32.9 (CH2), 31.8 (CH2), 31.6 (CH2), 31.4 (CH), 30.5 (CH2), 27.7 (CH2), 27.0 (3CH3), 20.5 (CH2),
19.4 (CH3), 19.1 (C), 17.1 (CH3), 12.2 (CH3), 12.1 (CH3); MS-ESI (m/z): 720.3 [M+Na]+; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C43H63O3N3Si: 698.4711, found: 698.4710.
Amino diol 30: At – 70 °C, a solution of 27 (346 mg, 0.5 mmol) in THF (10 mL) was treated with LiAlH4
(57 mg, 1.5 mmol, 3 equiv) for 2 h. TLC analysis indicated the complete consumption of the starting
material. The reaction was quenched with MeOH (5 mL) at -70 °C; NiCl2•6H2O (23 mg, 0.1 mmol, 0.2
equiv) and NaBH4 (156 mg, 4 mmol, 8 equiv) at 0 °C and the mixture was stirred at ambient
temperature for 14 h. Then the mixture was diluted with MeOH, concentrated under reduced
pressure, and purified through flash column chromatography on silica gel (PE/EA: 10/1 to 1/1) to give
diol 30 (247 mg, 74%) as a colorless syrup. Rf = 0.17 (silica gel, DCM/MeOH: 9/1); [α]D22 -24.1 (c 1.00,
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DCM); IR (film): 3365, 2932, 1729, 1462, 1427, 1110, 1087 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.64
– 7.53 (m, 4H), 7.46 – 7.34 (m, 6H), 5.09 – 5.01 (m, 1H), 4.36 (br s, 1H), 3.66 – 3.55 (m, 1H), 3.51 –
3.38 (m, 1H), 3.28 – 3.20 (m, 2H), 3.19 – 3.07 (m, 1H), 2.25 (t, J = 11.6 Hz, 1H), 2.14 – 1.97 (m, 2H),
0.97 (s, 9H), 0.89 (s, 3H), 0.86 (d, J = 6.2 Hz, 3H), 0.80 (d, J = 7.8 Hz, 3H), 0.78 (s, 3H);13C NMR (100
MHz, DMSO-d6) δ 140.5 (C), 135.2 (4CH), 133.85(2C), 129.8 (2CH), 127.8 (4CH), 120.8 (CH), 73.5 (CH),
72.9 (CH), 66.1 (CH2), 54.7 (CH), 53.5 (CH), 51.6 (CH), 49.0 (CH), 42.5 (CH2), 40.4 (CH2), 36.6 (CH), 35.9
(CH), 35.6 (C), 31.9 (CH2), 31.5 (CH2), 31.0 (CH2), 30.5 (CH), 29.4 (CH2), 29.1 (CH2), 26.8 (CH), 20.1
(CH2), 19.0 (CH), 18.7 (C), 17.3 (CH3), 14.0 (CH3), 12.7 (CH); MS-ESI (m/z): 672.4 [M+H]+; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C43H65O3NSi: 672.4806, found: 672.4802.
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Protected solanidine 35: To a solution of diol 29 (100 mg, 0.14 mmol) and DMAP (2.0 mg, 0.014
mmol, 0.1 equiv) in DCM/pyridine (2.0 mL/0.50 mL) was added MsCl (0.090 mL, 1.1 mmol, 8 equiv) at
0 °C. The resulting mixture was stirred at ambient temperature for 9 h, then quenched with a
saturated solution of NaHCO3 (5 mL), diluted with water (10 mL), and extracted with DCM (5 mL×3).
The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude was dissolved in MeCN (5 mL) and the solution was stirred at reflux for 7
h. The solvent was switched to MeOH (10 mL) and the resulting solution was treated with NaBH4 (42
mg, 1.1 mmol, 8 equiv) at ambient temperature for 10 h. The reaction was quenched with water,
diluted with MeOH, concentrated under reduced pressure, and purified through flash column
chromatography on silica gel (PE/EA: 6/1 to 2/1) to afford the protected solanidine 35 (51 mg, 54%)
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as a white solid. Rf = 0.50 (silica gel, PE/EA: 3/1); mp: 139.5-141.3 °C; [α]D -15.1 (c 0.45, DCM); IR
(film): 3070, 2929, 2856, 1472, 1427, 1261, 1110, 1087 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.70 – 7.64
(m, 4H), 7.45 – 7.32 (m, 6H), 5.12 (d, J = 5.1 Hz, 1H), 3.58 – 3.46 (m, 1H), 2.83 (dd, J = 10.2, 3.1 Hz, 1H),
2.59 (dt, J = 7.4, 6.4 Hz, 1H), 2.38 – 2.27 (m, 1H), 2.13 (dd, J = 13.3, 2.9 Hz, 1H), 1.95 – 1.87 (m, 1H),
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1.05 (s, 9H), 0.99 (s, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 8.7 Hz, 3H), 0.82 (s, 3H); C NMR (100
MHz, CDCl3) δ 141.3 (C), 135.8 (2CH), 135.7 (2CH), 134.8 (C), 134.8 (C), 129.4 (CH), 129.4 (CH), 127.4
(2CH), 127.4 (2CH), 121.1 (CH), 74.6 (CH), 73.2 (CH), 69.0 (CH), 63.0 (CH), 60.3 (CH2), 57.6 (CH), 50.1
(CH), 42.5 (CH2), 40.2 (CH2), 39.9 (C), 37.2 (CH2), 36.6 (CH), 33.4 (CH2), 32.0 (CH2), 31.9 (CH2), 31.6
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(CH), 31.3 (CH2), 31.1 (CH), 29.3 (CH2), 27.0 (3CH3), 20.9(CH2), 19.5 (CH3), 19.4 (CH3), 19.1 (C), 18.3
(CH3), 16.9 (CH3); MS-ESI (m/z): 636.4 [M+H]+; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C43H61ONSi:
636.4595, found: 636.4593.
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Solanidine (4): A solution of 35 (38 mg, 0.06 mmol) in THF (3.0 ML) was treated with TBAF (1.0 M, 1.0
mL, 1.0 mmol) at 50 °C for 2 h. The reaction was quenched with water, concentrated under reduced
pressure, and purified through column chromatography on silica gel (PE/EA: 5/2 to 2/1) to afford
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solanidine 4 (24 mg, 99%) as a white solid. Rf = 0.83 (silica gel, PE/EA: 1/1); mp: 208.3-209.5 °C; [α]D
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-20.8 (c 0.50, DCM); IR (film): 3246, 2927, 1453, 1372, 1053, 1009 cm-1; HNMR (400 MHz, CDCl3) δ
5.35 (d, J = 5.1 Hz, 1H), 3.57 – 3.46 (m, 1H), 2.91 – 2.81 (m, 1H), 2.68 – 2.57 (m, 1H), 2.36 – 2.15 (m,
2H), 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), 42.5 (CH2), 40.4 (C), 40.1 (CH2), 37.4 (CH2), 36.8 (CH), 36.8 (C), 33.5 (CH2), 32.2 (CH2), 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);
MS-ESI (m/z): 398.3 [M+H]+; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C27H43ON: 398.3417, found:
398.3416.
Protected 22-epi-solanidine 37: To a solution of diol 29 (100 mg, 0.14 mmol) and DMAP (2.0 mg,
0.014 mmol, 0.1 equiv) in DCM/pyridine (2.0 mL/0.50 mL) was added MsCl (0.090 mL, 1.1 mmol, 8
equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 7 h, then quenched with a saturated
solution of NaHCO3 (5 mL), and extracted with ether (2 mL×3). To the combined organic layers were
added sequentially MeOH (3.0 mL), NiCl2•6H2O (7.0 mg, 0.029 mmol, 0.2 equiv), and NaBH4 (42 mg,
1.1 mmol, 8 equiv) at 0 °C. The mixture was stirred at ambient temperature for 10 h and another
portion of NaBH4 (42 mg, 1.1 mmol, 8 equiv) was added. The reaction mixture was stirred for another
5 h, quenched with water, diluted with MeOH, concentrated under reduced pressure, and purified via
flash column chromatography on silica gel (PE/EA: 6/1 to 2/1) to furnish the protected
22-epi-solanidine 37 (34 mg, 38%) as a yellow gum and the protected solanidine 35 (9.1 mg, 10%). Rf
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= 0.33 (silica gel, DCM/MeOH: 15/1); [α]D -11.9 (c 0.30, DCM); IR (film): 3070, 2929, 2855, 1460,
1427, 1378, 1110, 864 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J = 6.0, 1.6 Hz, 4H), 7.44 – 7.31 (m,
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6H), 5.12–5.09 (m, 1H), 3.69–3.57 (m, 1H), 3.59–3.46 (m, 1H), 2.62 (d, J = 11.3 Hz, 1H), 2.51 (d, J = 9.8
Hz, 1H), 2.33 (t, J = 10.9 Hz, 2H), 2.13 (dd, J = 13.4, 3.0 Hz, 1H), 1.06 (d, J = 7.2 Hz, 1H), 1.05 (s, 9H),
0.99 (s, 3H), 0.88 (d, J = 7.1 Hz, 3H), 0.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.3 (C), 135.7 (2CH),
135.7 (2CH), 134.8 (2C), 129.4 (CH), 129.4 (CH), 127.4 (2CH), 127.4 (2CH), 121.0 (CH), 73.2 (CH), 67.5
(CH), 64.9 (CH), 60.7 (CH), 54.6 (CH), 50.1 (CH), 42.5 (CH2), 41.1 (C), 40.6 (CH2), 37.1 (CH2), 36.7 (CH),
35.4 (CH2), 32.3 (CH2), 31.8 (CH2), 30.6 (CH), 30.3 (CH2), 28.1 (CH), 27.0 (3CH3), 26.4 (CH2), 21.7 (CH2),
20.9 (CH2), 19.4 (CH3), 19.1 (C), 18.5 (CH3), 17.8 (CH3), 14.7 (CH3); MS-ESI (m/z): 636.4 [M+H]+; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C43H61ONSi: 636.4595, found: 636.4587.
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22-epi-Solanidine (6): A solution of 37 (10.0 mg, 0.016 mmol) in THF (1.0 ML) was treated with TBAF
(0.5 M, 1.0 mL, 0.5 mmol) at 60 °C for 4 h. The reaction was quenched with water, concentrated
under reduced pressure, and purified through column chromatography on silica gel (PE/EA: 5/2 to
2/1) to afford 22-epi-solanidine 6 (6.0 mg, 99%) as a white solid. Rf = 0.50 (silica gel, DCM/MeOH:
15/1); mp: 140.3-141.5 °C; [α]D22 -8.6 (c 0.30, DCM), −30.8 (c 0.11, MeOH) (ref. −35.6 (c 0.11, MeOH));
IR (film): 3566, 2925, 2867, 1456, 1374, 1361, 1060, 1011 cm-1; 1HNMR (400 MHz, pyridine-d5) δ 5.53
(d, J = 4.9 Hz, 1H), 4.02 – 3.91 (m, 1H), 3.88 – 3.79 (m, 1H), 2.79 (d, J = 11.2 Hz, 1H), 2.76 – 2.70 (m,
2H), 2.67 – 2.59 (m, 1H), 2.53 – 2.42 (m, 1H), 2.23 – 2.15 (m, 1H), 2.13 – 2.05 (m, 2H), 1.24 (d, J = 7.1
Hz, 3H), 1.17 (s, 3H), 1.08 (d, J = 7.1 Hz, 3H), 0.90 (s, 3H); 13C NMR (100 MHz, pyridine-d5) δ 142.5 (C),
121.7 (CH), 71.8 (CH), 68.2 (CH), 65.4 (CH), 61.7 (CH), 55.2 (CH), 54.3 (CH2), 51.0 (CH), 44.1 (CH2), 41.9
(C), 41.3 (CH2), 38.3 (CH2), 37.6 (C), 36.2 (CH), 33.1 (CH2), 31.4 (CH2), 31.2 (CH), 30.5 (CH2), 29.1 (CH),
27.0 (CH2), 22.8 (CH2), 21.8 (CH2), 20.1 (CH3), 19.0 (CH3), 18.7 (CH3), 15.2 (CH3); MS-ESI (m/z): 398.4
[M+H]+; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C27H43ON: 398.3417, found: 398.3414.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
10.1021/.
1
1H NMR spectra for known compounds, H and 13C NMR spectra of all new compounds (PDF),
crystallographic data for 18 (CIF).
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Acknowledgments
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We thank the National Natural Science Foundation of China (21272258, 21572248) for financial
support.
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