Stereoselective Synthesis of (-)-Verazine and Congeners via a Cascade Ring-Switching Process of Furostan-26-acid

Article abstract of DOI:10.1021/acs.orglett.0c00747

An efficient synthetic strategy for three natural seco-type cholestane alkaloids isolated from the Veratrum plants, based on commercially available naturally occurring and abundant (-)-diosgenin (1), as exemplified in the concise asymmetric synthesis of (-)-verazine (4), (-)-veramiline (5) (proposed structure), and its 22-epimer, (-)-oblonginine (6), is presented. This work highlights the application of a cascade ring-switching process of (-)-diosgenin to achieve the E-ring opening and construction of chiral six-membered lactone challenges in seco-type cholestane alkaloid synthesis. This approach enables the synthesis of related natural and nature-like novel cholestane alkaloids, opening up opportunities for more extensive exploration of cholestane alkaloid biology.

Full text of DOI:10.1021/acs.orglett.0c00747

pubs.acs.org/OrgLett
Letter
Stereoselective Synthesis of (−)-Verazine and Congeners via a
Cascade Ring-Switching Process of Furostan-26-acid
Yun Wang, Yong Shi, Wei-Sheng Tian, Pei Tang, Chunlin Zhuang, and Fen-Er Chen*
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ABSTRACT: An efficient synthetic strategy for three natural seco-
type cholestane alkaloids isolated from the Veratrum plants, based
on commercially available naturally occurring and abundant
(−)-diosgenin (1), as exemplified in the concise asymmetric
synthesis of (−)-verazine (4), (−)-veramiline (5) (proposed
structure), and its 22-epimer, (−)-oblonginine (6), is presented.
This work highlights the application of a cascade ring-switching
process of (−)-diosgenin to achieve the E-ring opening and
construction of chiral six-membered lactone challenges in seco-type
cholestane alkaloid synthesis. This approach enables the synthesis
of related natural and nature-like novel cholestane alkaloids,
opening up opportunities for more extensive exploration of
cholestane alkaloid biology.
art of our research interest has been directed at the
development of a general synthetic strategy for cholestane
P
alkaloids with particular emphasis on simplicity, efficiency, and
selectivity. (−)-Diosgenin (1),1 a commercially available natural
product, was viewed as a versatile platform to devise a
conceptionally novel divergent approach toward steroidal
alkaloids. To this end, we recently developed a cascade ring-
switching process for furostan-26-acids from (−)-diosgenin
acetate with E-ring opening and chiral six-membered lactone
ring formation as a key step in stereocontrolled synthesis of
solanidine (2),2 demissidine (3),3 and other seco-cholestane
alkaloids4 (Figure 1). This convenient and efficient activation
relay process for the cleavage of the C16−O bond in
(−)-diosgenin offers the important building block, a chiral
C16α-iodolactone core containing a cholestane ring, by
employing the intact (−)-diosgenin skeleton in rapid assembly
of the requisite segments in asymmetric synthesis of other
natural and nature-like steroidal alkaloids (Scheme 1).
Figure 1. Structures of (−)-diosgenin (1) and seco-cholastane alkaloids
(2−6).
As an initial foray into applications in natural steroidal alkaloid
synthesis, seco-cholastane alkaloids were chosen as our synthetic
targets, as exemplified by (−)-verazine (4),5 (−)-veramiline
(5),6 and its 22-epimer, (−)-oblonginine (6),7 a group of seco-
cholestane-type alkaloids isolated from various species of the
Veratrum family (Figure 1). The extraordinary range of
biological properties exhibited by this class of seco-cholestane
alkaloids, including antitumor, antimicrobial, and antinocicep-
tive activities,8 has attracted considerable levels of attention
from the medicinal and synthetic communities. However, due to
their scarcity in nature, limited pharmacological studies have
been employed on these seco-cholastane alkaloids and other
congeners. In our continuing efforts toward the synthesis of
biologically active steroidal alkaloids, we endeavor to develop
efficient strategies that enable the preparation of not only these
seco-cholastane alkaloids themselves but also various analogues
and derivatives for the detailed evaluation of their biological
Received: February 27, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00747
© XXXX American Chemical Society
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developed in our asymmetric synthesis of seco-cholastane
alkaloids (2 and 3).
Scheme 1. Cascade Ring-Switching Process of Furostan-26-
acid
(−)-Veramiline (5) and (−)-oblonginine (6) posed a
significant challenge with respect to diastereocontrol. However,
a semisynthesis study from 4 via an imine reduction pathway to
5 in a protocol reported by Kingston and co-workers9 provides a
straightforward but unattractive route due to very poor
diastereoselectivity.10 An attractive solution was found in a
tandem azide reduction/diastereoselective double reductive
amination, and several successful examples have been reported
in its application to the synthesis of deoxy aza sugars and
alkaloids.11 The azide reduction/stereoselective reductive
amination cascade reaction derived from 4 was envisaged to
lead to the asymmetric synthesis of 5 and 6, which could be an
ideal strategy in terms of both diastereoselectivity and step-
economy due to the two-step sequence as noted in our
retrosynthetic analysis.
Our synthesis commenced with the protection of the
diosgenin (1) to afford 11 as its TBDPS ether.1g The resulting
crude 11 reacted with Et3SiH in the presence of BF3·Et2O,12
leading to smoothly reductive cleavage of spiroketal to deliver
furostan-26-alcohol 12, which was directly subjected to Jones
oxidation to give furostan-26-acid 10 in 76% yield over three
steps. Subjection of 10 to the cascade bromo-lactonization
reaction with trifluoroacetic anhydride (TFAA) and lithium
bromide resulted in E-ring opening and C16 substitution of a
bromide ion within the substrate, thereby generating the
anticipated C16-bromolactone 9 in 78% yield in gram
quantities.
activities as well as structural activity relationship studies.
Starting from commercially available (−)-diosgenin (1), we
herein describe the application of a convenient entry to a novel
key chiral intermediate C16α-bromolactone through the
cascade ring-switching process of furostan-26-acid to the first
asymmetric synthesis of three natural seco-cholastane alkaloids
(4−6).
Our approach toward 4−6 is outlined in a retrosynthetic
format divergent in Scheme 2. A concise synthesis of 4 is realized
Scheme 2. Retrosynthetic Analysis of seco-Cholastane
Alkaloids (4−6)
With gram quantities of C16α-bromolactone 9 in hand, we
began to study the hydrogenolysis of its C16−Br bond (Scheme
3). From the outset, we were concerned that the reductive
debromination reaction may not exhibit regioselective control
during palladium-catalyzed hydrogenolysis (see Tables S1 in the
Supporting Information for details). However, when applying 10
atm of H2, the reaction occurred smoothly with the addition of
NaOAc as an additive under 10% Pd/C catalysis in dichloro-
Scheme 3. Synthesis of C16α-Bromolactone 9 by the Cascade
Bromo-lactonization Process
by cascade reduction/cyclization of azidoketone 7. The
azidoketone 7 is synthesized from lactone 8 by a regio- and
stereoselective functionalization sequence including lactone
reduction, tosylation, and azidation of the primary alcohol and
Dess−Martin oxidation of the secondary alcohol. Lactone 8
could, in turn, be accessible from bromolactone 9 through
reduction of the C16−Br bond, followed by epimerization of the
C25-Me via substrate control. The C16α-bromolactone core
structure of 9 could readily be constructed from 1 via furostan-
26-acid 10 by using the cascade ring-switching chemistry
B
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methane/methanol at room temperature for 7 h, resulting in the
formation of (25R)-lactone 14 in quantitative yield (Scheme 4).
diphenyl phosphorazidate provided diazide product 19 in 15%
yield and inseparable product 18 and phosphate 20 in 78% yield
by silica gel column chromatography. This depressed result
promoted us to opt to employ a stepwise approach for the
elaboration of 18.
Scheme 4. Synthesis of 22,26-Diol 16 through the
Epimerization of (R)-Configuration at C25
Next, the transformation of diol 16 into azido ketone 7 was
required, as shown in Scheme 5. Selective tosylation of the
primary C26-OH of 16 afforded tosylate 17, which, without
purification, was subjected to NaN3 substitution reaction to give
the azido alcohol 18 in 82% yield. Subsequent oxidation of 18
with Dess-Martin periodinane (DMP) yielded azidoketone 7 in
89% yield.
Having successful access to the requisite azidoketone 7, we
investigated the intramolecular Staudinger aza-Witting reac-
tion14 to convert the azidoketone 7 into the desired cyclic imine
21. Initially, our attempts to affect the cyclic imine formation
resulted in decomposition of starting 7, and only complex
mixtures were obtained. Therefore, we then turned to the
tandem azide hydrogenation/intramolecular cyclization of
azidoketone 7 as an alternative tactic (see Table S2 in the
Supporting Information for details). To our delight, treatment of
7 with Raney Ni in methanol under a balloon pressure of H2 at
40 °C initiated this transformation to afford the desired cyclic
imine 21 in 84% yield. Upon treating 21 with tetrabutylammo-
nium fluoride (TBAF), the cleavage of the TBDPS ether residue
smoothly proceeded to produce (−)-verazine (4) in 86% yield
(Scheme 6). All the IR, H, and 13C NMR data for synthetic
1
Treating (25R)-lactone 14 with anhydrous K2CO3 in methanol
at 50 °C for 3 h completely epimerized the configuration from
(R) to (S) to provide a mixture (∼3:1) of (25S)-lactone 8 and
the open-chained methyl ester 15, which was subjected to
lithium aluminum hydride (LAH) reduction without separation
to afford 22,26-diol 16 in an overall yield of 94% over the two
steps.
Scheme 6. Formal Synthesis of (−)-Verazine (4)
We continued with the construction of the azidoketone unit,
as illustrated in Scheme 5. Initial attempts at the conversion of
diol 16 into the azidoalcohol 18 in a one-step manner using a
Merck azidation13 were unsucessful. Treatment of 16 with
Scheme 5. Synthesis of Azidoketone 7
(−)-4 were identical to that reported for the natural product
(see Tables S5−6 in the Supporting Information for
details).5a,d,9 Additionally, the specific rotation of
24
(−)-4[[α]D - 72.0 (c 1.50, MeOH)] was in good agreement
26
with [[α]D −65.0 (c 1.50, MeOH)], which confirmed the
stereoconfiguration of (−)-verazine (4) assigned by Kingston
and co-workers.9
As noted in our retrosynthetic analysis, the azidoketone 7
could serve as a common intermediate for the efficient synthesis
of (−)-5 and (−)-6, as shown in Scheme 7. A novel procedure
for a one-pot three-step sequence including azide reduction,
ketone amine cyclization, and imine reduction by treatment of 7
with NaBH4 in the presence of NaBH4/NiCl2·6H2O in
methanol under mild conditions for 4 h resulted in the
formation of the desired (−)-veramiline TBDPS ether 22 and
its 22-epimer, (−)-oblonginine TBDPS ether 23, which were
isolated in 25 and 45% yield, respectively, by silica gel column
chromatography. The structures of 22 and 23 were
unambiguously confirmed by X-ray crystallographic analysis
(Scheme 7 and Tables S3 and S4). In the final step of the
C
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Scheme 7. Formal Synthesis of (−)-Veramiline (5) and
(−)-Oblonginine (6)
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00747.
Detailed experimental procedures and 1H and 13C NMR
spectra of all new compounds (PDF)
Accession Codes
CCDC 1900504−1900505 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Fen-Er Chen − Engineering Center of Catalysis and Synthesis for
Chiral Molecules, Fudan University, Shanghai 200433, China;
Shanghai Engineering Center of Industrial Asymmetric Catalysis
for Chiral Drugs, Shanghai 200433, China; West China School
of Pharmacy, Sichuan University, Chengdu 610041, China;
orcid.org/0000-0002-6734-3388; Email: rfchen@
fudan.edu.cn
Authors
Yun Wang − Engineering Center of Catalysis and Synthesis for
Chiral Molecules, Fudan University, Shanghai 200433, China;
Shanghai Engineering Center of Industrial Asymmetric Catalysis
for Chiral Drugs, Shanghai 200433, China
Yong Shi − Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China; orcid.org/
0000-0002-7887-3050
Wei-Sheng Tian − Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Pei Tang − West China School of Pharmacy, Sichuan University,
Chengdu 610041, China
Chunlin Zhuang − Engineering Center of Catalysis and Synthesis
for Chiral Molecules, Fudan University, Shanghai 200433,
China; Shanghai Engineering Center of Industrial Asymmetric
Catalysis for Chiral Drugs, Shanghai 200433, China;
orcid.org/0000-0002-0569-5708
synthesis, compounds 22 and 23 were treated with TBAF, which
chemoselectively afforded cleavage of the TBDPS ether and
produced (−)-veramiline (5) (proposed structure) and
(−)-oblonginine (6) in 92 and 90% yield, respectively. The
specific rotations, [α]D25, of synthetic (−)-veramiline (5)
(proposed structure), −43.5 (c 0.7, MeOH), compared to that
of synthetic product (−)-5, −43 (c 0.7, MeOH),9 and
(−)-oblonginine (6), −37.2 (c 1.17, MeOH), compared to
that of natural product (−)-6, −40.7 (c 0.11, CHCl3),7a were
identical. Surprisingly, comparison of the spectroscopic data of
synthetic (−)-5 with those reported by Kingston indicated a few
differences,9 especially in the 13C NMR data regarding C16,
C17, and C24−C27 (see Tables S7 and S8 in the Supporting
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00747
Notes
1
Information for details). The H and 13C NMR spectra and
The authors declare no competing financial interest.
specific rotation of the synthesized (−)-oblonginine (6) were in
good agreement with those of natural (−)-6, as reported by
Kadoto and co-workers in 1995 and Salder and co-workers in
1998 (see Tables S9 and S10 in the Supporting Information for
details).7
In summary, we utilized our TFAA/LiBr-promoted cascade
bromo-lactonization process of the furostan-26-acid to yield a
chiral C16α-bromolactone building block with high regio- and
stereoselectivity in facile asymmetric synthesis of naturally
occurring seco-type cholestane alkaloids. We believe that the
described strategy and methodologies should be widely
applicable to the asymmetric synthesis of other related
cholestane alkaloids. These studies are currently underway in
our laboratory and will be reported in due course.
ACKNOWLEDGMENTS
We thank Professor Jing-Han Gui (Shanghai Institute of
Organic Chemistry) for helpful discussions.
■
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