Synthesis of Demissidine and Solanidine

Article abstract of DOI:10.1021/acs.orglett.6b01320

Demissidine and solanidine, two steroidal alkaloids, are synthesized in eight steps from tigogenin acetate and diosgenin acetate, respectively, which involve the replacement of three C-O bonds with C-N bonds. Key transformations include a cascade ring-switching process of furostan-26-acid, an epimerization of C25, an intramolecular Schmidt reaction, and an imine reduction/intramolecular aminolysis process.

Full text of DOI:10.1021/acs.orglett.6b01320

Letter
pubs.acs.org/OrgLett
Synthesis of Demissidine and Solanidine
Zhi-Dan Zhang, Yong Shi,* Jing-Jing Wu, Jing-Rong Lin, and Wei-Sheng Tian*
‡
,†
†
‡
,†
†Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
‡
Department of Chemistry, College of Life Sciences and Environment, Shanghai Normal University, 100 Guilin Road, Shanghai
200234, China
*
S Supporting Information
ABSTRACT: Demissidine and solanidine, two steroidal
alkaloids, are synthesized in eight steps from tigogenin acetate
and diosgenin acetate, respectively, which involve the
replacement of three C−O bonds with C−N bonds. Key
transformations include a cascade ring-switching process of
furostan-26-acid, an epimerization of C25, an intramolecular
Schmidt reaction, and an imine reduction/intramolecular
aminolysis process.
10
teroidal alkaloids and their glycosides, which occur in many
ring fragmentation 1,3-dipolar cycloaddition approach. Only
S
plants of the Solanaceae, are known to possess various
two syntheses of 4 from 2 and from isorubijervine were
11
bioactivities and structures, thus drawing great interest from
reported, both in low yields. Herein, we report an eight-step
synthesis of 3 and 4 with the 27C intact skeletons of steroidal
sapogenins.
1
researchers. Among these alkaloids, solasodine (1, Figure 1)
Compounds 3 and 4 differ from steroidal sapogenins in two
aspects: the configuration of C25 and the arrangement of the
EF rings. The EF rings of steroidal sapogenins are 5,6-
spiroketals with two oxygen atoms, while those in 3 and 4 are
5
,6-fused bicycles with a nitrogen atom at brighthead. Thus, we
needed to replace three C−O bonds (C16−O, C22−O, and
C26−O) with C−N bonds and to epimerize the configuration
of C25. We envisioned that the C26−N bond of 3/4 would be
constructed via an intramolecular N-alkylation and the C22−N
bond would be established stereoselectively via a Schmidt
reaction of azide 5 followed by a substrate-controlled reduction
of the resulting imine (Scheme 1). Azide 5 would be prepared
from iodide 6 through a substitution of C16α-I with sodium
azide and an epimerization of C25. Iodide 6, in turn, would be
prepared by a cascade ring-switching process of furostan-26-
acid derived from tigogenin acetate (7) or diosgenin acetate
Figure 1. Structures of demissidine (3) and solanidine (4).
12
and tomatidenol (2) are known to act as natural insect
(
8), a method we recently developed.
Our synthesis of demissidine (3) was depicted in Scheme 2.
deterrents, have antimicrobial properties, can inhibit acetylcho-
2
linesterase, and disrupt cell membranes. Demissidine (3) and
Furostan-26-acid 9 was prepared from 7 via a reduction−
oxidation process, and was then treated with trifluoroacetic
anhydride/lithium iodide to afford iodide 6 in high yield.
solanidine (4), which are two cholestane alkaloids isolated from
3
several potato species including Solanum demissum, Solanum
4
5
acaule, and Solanum tuberosum, mainly present as glycosides,
Treated with NaN in DMF at 65 °C, 6 underwent azide-
6
3
can inhibit proliferation and exhibit obvious antitumor effect.
substitution smoothly, delivering 10 in 93% yield. Epimerizing
Demissidine (3) was synthesized from the related steroida7l
the configuration of C25 from R to S was then performed, upon
alkaloid dihydrotomatidine by Kuhn and co-workers in 1952
12a
8
treatment with K CO (10 equiv) in MeOH at 45 °C for 5 h,
2 3
and later by Sato and Latham. In 1963 Adam and Schreiber
to give 5 in 90% on the multigram scale.
prepared 3 from pregnenolone acetate by addition of 2-lithio-5-
methylpyridine followed by hydrogenation and Hofmann−
9
Lo
̈
ffler−Freytag cyclization. Recently, Brewer and co-workers
Received: May 6, 2016
reported an efficient synthesis of 3 from epiandrosterone by a
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01320
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
15
Scheme 1. Synthetic Plan for Demissidine and Solanidine
under the reaction conditions. Similarly, subjection of 10 to
the same conditions caused epimerization at C25, giving a 1/2
inseparable mixture of 13 and 25-epi-13. Lowering the amount
of SOCl and using other methods of preparing HCl solution
2
could not inhibit the epimerization. Attempts to convert the
unwanted 25-epi-13 to 13 also failed as the C25 is now on a
flexible chain where the configurational bias of the C25-epimers
no longer exists.
Reduction of the imine group in 13 and 25-epi-13 (NaBH4,
EtOH, rt) was therefore performed, and the spontaneous
intramolecular aminolysis of the amino-ester was observed,
16
forming a small amount of lactam 14. Heating at reflux drove
the reaction to completion, giving 14 and its 25-epimer in 57%
and 28% yield, respectively. The stereochemistry of C22 was
assigned as R by 2D NOESY analysis (NOEs between C21-Me
and C22−H, and between C16α-H and C22−H), thus
confirming that the hydride approached the imine from the
less hindered face. Treating 25-epi-14 with various bases
(
K CO , DBU, NaH, LiHMDS, etc.) could not afford 14 in a
With 5 in hand, focus turned to stereoselective construction
of the required C16N−C22 bond. Both 5 and 3 are R-
configured at C22. Retaining the configuration might be
troublesome during a routine method involving the reduction
of the C16-azide to amine and the transformation of the C22−
O to a leaving group and the intramolecular substitution.
However, it would be more feasible to wipe its stereochemistry
by forming an imine and then to restore it through a substrate-
controlled reduction. Ideally, the imine could be reached
2 3
reasonable yield.
Reduction of the lactam in 14 to an amine was investigated.
To our surprise, treating 14 with LiAlH (rt to reflux in THF)
4
only gave demissidine in low yield. Later, reduction of 14 with
Red-Al (sodium bis(2-methoxyethoxy)aluminumhydride) in
toluene at ambient temperature cleanly gave 3 in 74% yield.
The analytical data of synthetic 3 matched with those reported.
Likewise, solanidine 4 was synthesized from diosgenin
acetate 8 (Scheme 3). Iodide 6 (with C5−C6 double bond)
was prepared from 8 in three steps and 77% yield. Azide-
substitution of C16α-I and epimerization of C25 followed by
the intramolecular Schmidt reaction gave imino-ester 16, which
13
directly from 5 through an intramolecular Schmidt reaction
triggered by forming a cation at C22.
12a
We then looked for conditions that could activate C22 and
thus trigger the designed Schmidt reaction. It was well-known
that lactones could be opened with HBr or HCl to afford the
was sequentially reduced with NaBH and Red-Al, providing
solanidine 4 in 18% overall yield from 6. The analytical data of
synthetic 4 matched with those reported.
4
14
corresponding ω-halo acids or esters. Under these conditions,
the intramolecular nucleophilic azido group nearby would
outdo the ambient halogen ions in attacking the electrophilic
site. After many attempts, we found this hypothesis worked.
Treating 5 with SOCl in MeOH (SOCl /MeOH (1/6) in situ
In summary, we developed an eight-step synthetic route to
demissidine and solanidine from tigogenin acetate (7) and
diosgenin acetate (8). Key transformations include the cascade
ring-switching process of furostan-26-acid, the intramolecular
Schmidt reaction of azido-lactones 5/15 to provide imino-
esters 13/16, and the stereoselective reduction/intramolecular
aminolysis of 13/16 to give lactams 14/17. It was also
noteworthy that our synthesis minimized the use of protecting
groups except the acetate in starting materials. Applying the
2
2
generates a solution of HCl in MeOH) at ambient temperature
delivered the desired imine 13 in good yield, and more
importantly, the exposed C3-OH was not affected, thus
avoiding the use of protecting groups. We soon found the
product was not a single isomer, but a 2/1 inseparable mixture
of 13 and its 25-epimer, indicating partial epimerization at C25
Scheme 2. Eight-Step Synthesis of Demissidine from Tigogenin Acetate
B
DOI: 10.1021/acs.orglett.6b01320
Org. Lett. XXXX, XXX, XXX−XXX

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ASSOCIATED CONTENT
Supporting Information
■
*
S
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01320.
Tetrahedron Lett. 2014, 55, 4639−4642. (b) Wu, J.-J.; Shi, Y.; Tian, W.-
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1
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1
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AUTHOR INFORMATION
Corresponding Authors
■
*
*
(
E-mail: shiong81@sioc.ac.cn (Y.S.).
E-mail: wstian@sioc.ac.cn (W.-S.T.).
Notes
Miftakhov, M. S. Tetrahedron 2013, 69, 9540−9543. (b) Wolfe, S.;
Wilson, M.-C.; Cheng, M.-H.; Shustov, G. V.; Akuche, C. I. Can. J.
Chem. 2003, 81, 937−960. (c) Kad, G. L.; Kaur, I.; Bhandari, M.;
Singh, J.; Kaur, J. Org. Process Res. Dev. 2003, 7, 339−340.
(
The authors declare no competing financial interest.
1
15) The H NMR of 13 and 25-epi-13 were almost the same, except
the signals of methyl ester. The chemical shift of the methoxyl group in
3 is 3.66 ppm and in 25-epi-13 is 3.65 ppm. The ratio of the two
epimers was thus identified.
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990, 31, 1439−1444. (b) Choi, J.-R.; Han, S.; Cha, J. K. Tetrahedron
Lett. 1991, 32, 6469−6472.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
21272258, 21572248) for financial support.
1
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(
1
(
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DOI: 10.1021/acs.orglett.6b01320
Org. Lett. XXXX, XXX, XXX−XXX