Highly efficient and scalable synthesis of clionamine D

Article abstract of DOI:10.1021/ol500727c

Herein we describe an efficient and scalable synthesis of clionamine D (4), a special member with autophagy bioactivity and an unprecedented spirobislactone side chain in the novel aminosteroid clionamines. This synthesis features a quick access to α-methylene-γ-lactone 8 and a Mn(OAc)₃-mediated radical [3 + 2] reaction to assemble the unique spirobislactone unit. Clionamine D (4) can also serve as a key synthetic precursor to other clionamine members.

Full text of DOI:10.1021/ol500727c

Letter
pubs.acs.org/OrgLett
Highly Efficient and Scalable Synthesis of Clionamine D
Sha-Sha Wang, Yong Shi,* and Wei-Sheng Tian*
The Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Herein we describe an efficient and scalable
synthesis of clionamine D (4), a special member with autophagy
bioactivity and an unprecedented spirobislactone side chain in
the novel aminosteroid clionamines. This synthesis features a
quick access to α-methylene-γ-lactone 8 and a Mn(OAc)3-
mediated radical [3 + 2] reaction to assemble the unique
spirobislactone unit. Clionamine D (4) can also serve as a key
synthetic precursor to other clionamine members.
ighly efficient synthesis of natural products with
diversified structures and bioactivities is still a challenging
making them potentially interesting drug leads for a variety of
human diseases.3 Recently, Andersen and co-workers reported
the synthesis of clionamine B from tigogenin (5) in order to
facilitate the biological evaluation and SAR studies on the
clionamine family.3a However, the low synthetic efficiency,
along with the uniqueness of the structures, provoked our
interest in their synthesis.
The key challenge in the synthesis of clionamine D (4) lies in
the stereoselective construction of the spirobislactone unit.
There are no efficient methods reported prior to our study. As
shown in Scheme 1, it was envisioned that 4 can be obtained by
the reductive amination3a,4 of bislactone 7. For the key
spirobislactone unit in 7, we postulated that it might ideally
be installed by a [3 + 2] reaction directly from the unsaturated
lactone 8. In turn, 8 could be derived from lactone 9 via
dehydrogenation. In contrast to Andersen’s five-step synthesis
of γ-lactone (6) (16% overall yield) from tigogenin (9) using
traditional CrO3-mediated degradation technology,5 the new
procedure developed in our group would allow one-step
preparation of γ-lactone 9 and its analogues from steroidal
sapogenins including tigogenin on a large scale, which served as
one of our contributions to the resource chemistry.6
H
task for synthetic chemists. This is likely due to the fact that
while natural products have been and continue to be an
important source for the discovery and development of new
medicine and agricultural agents, the shortage of natural
compounds seriously retards further study on their bioactiv-
ities.1 Herein, we report an efficient and scalable synthesis of
clionamine D in a high overall yield (51% over 10 steps). As a
special representative member with an unprecedented
spirobislactone side chain in the novel aminosteroid clionamine
family, clionamine D (4) can be considered a biodegradation
product of natural clionamines A−C (1−3); thus, it could also
serve as a key synthetic precursor to other clionamine family
members (Figure 1).
Clionamines A−D were isolated by Andersen and co-workers
from the crude MeOH extract of the sponge Cliona celata,
collected in South African marine waters, to look for new
chemical genetics tools to explore autophagy.2 Biologically,
clionamine A (1) and B (2) stimulate autophagy in human
breast cancer MCF-7 cells at low micromolar concentrations,
As depicted in Scheme 2, through an iodine induced
abnormal Baeyer−Villiger oxidation (AcOOH, 10 mol % I2,
10 mol % H2SO4, HOAc, rt, 24 h; KOH, EtOH, rt, 12 h),
tigogenin was degraded directly into α-methyl-γ-lactone 9 on
the 100 g scale in 89% yield. Then its 3β-OH was protected as
robust TBDPS ether to provide lactone 10. Unexpectedly, the
conversion of 10 into α-methylene-γ-lactone 8 employing
routine methods met with some trouble due to the difficulty in
introducing a leaving group (such as Br, I, and SePh) at C-20.
The low yield in preparing C-20 substituted lactone 11
compelled us to resort to less conventional methods.
Ultimately, it was found that a Schenck ene reaction7 of the
Figure 1. Structures, biogenesis, and our synthetic project of
clionamines A−D (1−4).
Received: March 9, 2014
Published: March 25, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
reducing the peroxide bond of intermediate 13 with Me2S in
70% yield on the 50 mg scale. Unluckily, the yield dropped
dramatically to 20−30% on the 500 mg scale. Upon
optimization, we found that replacing DCM with cyclohexane
gave a stable 50−60% yield of 14 on gram scale, and using
NaHCO3 (10 wt %) as an additive further improved the yield
to a reproducible 90% yield. Meanwhile, the treatment of
peroxy hemiacetal 13 with Ac2O and Et3N9 in situ generated α-
methylene lactone 8 in 93% yield on the multigram scale. In
this manner, we solved the challenging problem of converting
10 into 8.
Scheme 1. Retrosynthetic Analysis of Clionamine D (4)
With a sufficient amount of 8 and 14 in hand, initially, we
attempted to introduce another two-carbon unit through a
[3.3]-rearrangement of 1410 but, unfortunately, failed to obtain
any positive outcome at the current stage.11 We then focused
on the chemistry of the electron-deficient double bond of 8.
In 1968, Bush and Heiba simultaneously demonstrated that,
when subjected to a refluxing solution of Mn(OAc)3 in AcOH,
alkyl or aryl substituted olefins were transformed into γ-lactone
via a radical pathway in low to excellent yield.12 However,
employing this method in natural product synthesis has not
been described since its initial disclosure, although Mn(III)-
based oxidative free-radical cyclizations and annulations have
been extensively investigated by Snider, Bertrand, Chuang, and
others.13 Obviously, it would be extremely efficient to assemble
the second γ-lactone of the spirobislactone unit in clionamine
D from an exocylic double bond. Attracted by the directness of
this method, we decided to explore the possibility of assembling
the spirobislactone unit from 8 by this radical [3 + 2] reaction.
To our great delight, according to Bush’s procedure,12a
treatment of 8 with Mn(OAc)3 and Ac2O in refluxing AcOH
successfully delivered the desired spirobislactone 15, albeit only
in 15% yield. The structure and stereochemistry of 15 was
assigned through its NMR spectroscopic analysis (1H, 13C, and
2D NOESY) and further confirmed by the X-ray crystallog-
raphy of a later intermediate 7. After investigating the effect of
solvent and additive to the reaction, we eventually confirmed
Heiba’s procedure12e to include the optimal conditions:
refluxing the solution of 8 and Mn(OAc)3 in HOAc in the
presence of KOAc for 2−3 h furnished 15 in excellent yield on
a multigram scale. Clearly from the less hindered face the
complexed free-radical A approached α-methylene lactone 8
and the resultant radical B underwent lactonization14 to provide
15 in a substrate-controlled manner (Scheme 3).
Scheme 2. Preparation of α-Methylene Lactone 8 on
Multigram Scale
In the final stage, removal of the TBDPS group by treating
15 with aqueous HF in CH3CN at 60 °C was followed by a
Dess−Martin oxidation to provide ketone 7 in high yield. X-ray
crystallography of 7 confirmed that the desired spirobislactone
was correctly constructed during the crucial radical [3 + 2]
reaction. Reductive amination of 7 using NaBH3CN and
NH4OAc gave clionamine D (4) in 80% yield, along with 3-epi-
clionamine D in 14% yield. It was noteworthy that clionamine
D (4) was isolated as CF3CO2H or HCl salts through column
chromatography using reversed phase silica gel, and more than
500 mg natural product had been prepared in our laboratory.
The spectroscopic properties of the synthetic clionamine D (as
CF3CO2H salt) are consistent with those reported in the
literature.15
vinyl ether 12 would be a better choice for the conversion of 10
into 8.
DIBAL-H reduction of 10 at −78 °C, followed by
dehydration in the presence of a catalytic amount of p-
toluenesulfonic acid/polyvinylpyridine (PVP) in refluxing
toluene, provided vinyl ether 12 in excellent yield.8 The
Schenck ene reaction of vinyl ether 12 with singlet oxygen (O2,
0.5 mol % meso-tetraphenylporphine, sunlamp, 0 °C) in
dichloromethane (DCM) smoothly provided hemiacetal 14
(it can also serve as another key synthetic precursor) after
In conclusion, we have achieved the first synthesis of
clionamine D (4) in 10 steps from tigogenin in an overall yield
of 51%, which provides a solid base for the synthesis of other
natural members of the clionamine family. The main features
involved in this highly efficient synthesis include a convenient
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Organic Letters
Letter
(c) Marker, R. E.; Turner, D. L.; Wagner, R. B.; Ulshafer, P. R.;
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Scheme 3. Completion of the Synthesis of Clionamine D
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acidic catalyst, so the dehydration step requires immediate removal of
the solid TsOH/PVP through filtration and subjection to purification.
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Jeon, H. B. Tetrahedron Lett. 2011, 52, 6578.
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has been reported to date. Currently, all the attempts (Claisen,
Johnsonon−Claisen, Ireland−Claisen, Eschenmoser−Claisen, etc.) on
14 gave complex reaction mixtures, and we are working on milder
procedures.
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(b) Heiba, E. I.; Dessau, R. M.; Koehl, W. J. J. Am. Chem. Soc. 1968,
90, 5905. (c) Heiba, E. I.; Dessau, R. M.; Koehl, W. J. J. Am. Chem. Soc.
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onlinelibrary.wiley.com/doi/10.1002/047084289X.rm018.pub2/
abstract (accessed Feb 6, 2014).
(14) The detailed mechanism of the conversion of a radical such as B
to the final lactone has not been elucidated. Three possible pathways
were provided in Supporting Information referring to the research of
Fristad and co-workers. (a) Fristad, W. E.; Peterson, J. R. J. Org. Chem.
1985, 50, 10. (b) Fristad, W. E.; Peterson, J. R.; Ernst, A. B. J. Org.
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(15) Clionamine D in free base form is insoluble in most of the
deuterated solvents except pyridine-d5, and the natural clionamine D
was isolated as the CF3CO2H salt. For the ease of future comparison,
we also provided the NMR spectrum of clionamine D as a free base in
pyridine-d5 (see Supporting Information).
three-step sequence to α-methylene lactone from γ-lactone and
a Mn(OAc)3-mediated radical [3 + 2]-cycloaddition (lactoniza-
tion) to install the spirobislactone unit of clionamine D. Our
work also provides the first successful example of a Mn(OAc)3-
mediated radical [3 + 2] reaction in the context of complex
natural product synthesis, which may be applicable to the
synthesis of other spirobislactone containing natural products.
A collective synthesis of other natural members and analogues
of the clionamine family is ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, spectral data, 1H and 13C NMR spectra of
all the new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*Email: shiong81@sioc.ac.cn.
*Email: wstian@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
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