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Isolation, biosynthesis, and chemical syntheses of the hasubanan and acutumine
alkaloids: A historical perspective
Denise C. Grünenfelder, Sarah E. Reisman, Raul Navarro
PII:
S0040-4020(23)00511-2
DOI:
https://doi.org/10.1016/j.tet.2023.133709
Reference:
TET 133709
To appear in:
Tetrahedron
Received Date:
1 October 2023
Revised Date:
17 October 2023
Accepted Date:
18 October 2023
Please cite this article as: Grünenfelder DC, Reisman SE, Navarro R, Isolation, biosynthesis, and
chemical syntheses of the hasubanan and acutumine alkaloids: A historical perspective,
Tetrahedron
(2023), doi:
https://doi.org/10.1016/j.tet.2023.133709
.
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1
Isolation, Biosynthesis, and Chemical Syntheses of the Hasubanan and Acutumine Alkaloids:
A Historical Perspective
Denise C. Grünenfelder,
1
Sarah E. Reisman,
1
Raul Navarro
2
*
1
Division of Chemistry and Chemical Engineering, California Institute of
Technology, Pasadena,
California 91125, United States
2
Department of Chemistry, Occidental College, Los Angeles, California 90041, United States
Corresponding author email address: rnavarro@oxy.edu
Corresponding author mailing address: 1600 Campus Road; Ma
il Code M
-
5, Norris Hall of
Chemistry; Los Angeles, CA 90041
Abstract
The hasubanan and acutumine alkaloids comprise a large collection of aza
-
propellane natural
products that possess varying degrees of structural complexity and biological activity. Since
their
initial structural elucidation in the 1960s, these alkaloids have garnered considerable attention from
the synthetic community and have remained the subject of numerous studies aimed toward
understanding their biosynthetic origins and synthesizing t
heir complex architectures. Herein, we
review the rich history associated with their isolation, characterization, biosynthetic origins, and
chemical synthesis, with an emphasis on the range of synthetic strategies that have been
implemented to access their
aza
-
propellane framework. The unique features and history of each
class of aza
-
propellanes are discussed in two separate sections of this account.
Keywords:
hasubanan, acutumine, propellanes, alkaloids, total synthesis
1. The Hasubanan Alkaloids
1.1. Intr
oduction
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2
The hasubanan alkaloids represent a large collection of natural products isolated from the
Menispermaceae
family of plants, which have long been used in traditional Chinese medicine for
the treatment of pain, arthritis, fever, and many other illne
sses.
1
Since their initial discovery in the
1920s, over 80 members of this collection of alkaloids have been isolated to date.
2
–
4
Each of these
compounds can be structurally characterized by the presence of a densely functionalized [4.4.3]
aza
-
propellane
framework (
3
,
rings B/C/D,
Figure 1), and can be further organized based on the
oxidation pattern that adorns their propellane core. Cepharamine (
1
) and 8
-
demethoxyrunanine (
2
)
constitute the least oxidized hasubanan alkaloids, due to their lack of a funct
ional group at the C8
carbon. Introduction of a C8 oxygen functionality leads to natural products bearing the
hasubanonine oxidation pattern, such as hasubanonine (
4
), aknadinine (
5
), runanine (
6
), and
delavayine (
7
). Additional oxidation at the C10 carbon
is characteristic of the oxo
-
bridged
propellane alkaloids, including metaphanine (
8
), longanine (
9
), periglaucine A (
10
), and
stephanaberrine (
11
).
Since their initial structural elucidation in the 1960s, the hasubanan alkaloids have garnered
considerable
attention from the synthetic community in part due to their resemblance to morphine.
Indeed, the hasubanan and morphinan frameworks differ primarily in their D ring composition:
whereas
3
contains a C14
-
N bond to form a pyrrolidine, the morphine backbone
presents the
analogous C9
-
N
-
linked piperidine ring. Additionally, these natural products are of opposite
enantiomeric series; as a result, it has been speculated that the unnatural enantiomers of the
hasubanan alkaloids might exhibit analgesic activity.
5
A
lthough studies aimed at assessing this
hypothesis have yet to be reported, several naturally occurring hasubanans display promising
biological properties. For instance, the oxo
-
bridged propellanes periglaucine A (
10
) and longanine
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3
(
9
) were found to demons
trate anti
-
hepatitis B virus activity and selective
δ
-
opioid receptor
binding affinity, respectively.
6
As a result of their unique molecular architecture and potential biological applications, the
hasubanans have been the subject of numerous synthetic end
eavors for nearly 60 years. Herein,
we take a comprehensive look at
the diverse array of strategies employed
over the last six decades
to target their propellane framework. Preceding the discussion of these reports, a brief history of
the hasubanan family
of natural products is presented, including their isolation and biosynthetic
origins.
7
Figure 1.
Representative members of the hasubanan alkaloids.
1.2. Isolation
In 1924, Kondo and coworkers described the isolation of metaphanine (
8
), an oxo
-
bridged
has
ubanan alkaloid.
8
Its structure was not elucidated until 1964, when Takeda and coworkers
characterized the compound by infrared (IR) and 1D nuclear magnetic resonance (NMR)
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4
spectroscopy, as well as through a number of derivatization studies.
9
Specifically,
degradation of
8
under reducing conditions delivered anthracene derivative
12
, a structural motif observed to arise
from the degradation of morphine alkaloids (Scheme 1). In addition, sequential reduction of
8
afforded hasubanan
13
,
a known compound whose
enantiomer
ha
d previously
been prepared from
a codeinone intermediate. Using these spectroscopic techniques and synthetic derivatizations,
Tomita and coworkers determined the structures of cepharamine (
1
)
10
and hasubanonine (
4
).
11
Tomita’s assignments w
ere validated in 1968, when Kupchan and coworkers obtained an X
-
ray
crystal structure of the brosylate derivative of aknadinine (
5
).
12
As novel hasubanan alkaloids
began to emerge, 2D NMR techniques and mass spectrometry became important tools for more
efficient structural determination. For example, the structure of runanine (
6
) was ascertained by
extensive NOE experiments. Additionally
, the most abundant ion peak observed in the mass
spectrum of
6
was
m
/
z
= 315, which corresponds to loss of its ethylamine chain.
13
This type of
fragmentation is characteristic of propellane alkaloids bearing the hasubanonine framework.
4
Taken together, th
ese pioneering studies laid the foundation for the characterization of
subsequently discovered hasubanan alkaloids.
Scheme 1.
Structural elucidation of metaphanine (
8
).
In more recent years, a significant number of natural products comprising the metap
hanine
oxidation pattern have been discovered: nearly 30 oxo
-
bridged hasubanans have been reported in
the last 20 years alone.
6,14
–
18
Interestingly, members of the metaphanine
-
type alkaloids are the only
hasubanans reported to demonstrate medicinal propert
ies (
vide supra
). Moreover, the recent
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5
emergence of oxo
-
bridged hasubanans in the literature raises numerous questions regarding their
biosynthetic relationship to their less oxidized congeners.
1.3. Biosynthesis
The structural similarities between the mor
phinan and hasubanan alkaloids have been exploited
to examine the biosynthesis of hasubanonine (
4
). Specifically, it is known that morphine is derived
from the coupling of two tyrosine building blocks, which initially generates an isoquinoline
intermediate
.
19
With these considerations in mind, Battersby and coworkers conducted feeding
experiments with
14
C
-
labeled tyrosine and isoquinoline derivatives bearing an array of arene
oxidation patterns,
20
which revealed that the hasubanan framework is indeed derive
d from two
different tyrosine
-
based building blocks. Moreover, Battersby concluded that the C ring of
5
originates from trioxygenated intermediate
14
(Scheme 2). Importantly, the oxidation of tyrosine
occurs prior to isoquinoline formation: feeding studies
using analogous mono
-
and dioxygenated
isoquinolines determined that these precursors are not elaborated to the natural product.
Scheme 2.
Proposed biosynthesis of the hasubanan alkaloids.
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