Concise Asymmetric Syntheses of Streptazone A and Abikoviromycin**

Article abstract of DOI:10.1002/anie.202101439

Streptazone A and abikoviromycin are alkaloids that both feature an unusual arrangement of reactive functionalities within a compact tricyclic ring system. Here, we report a highly concise asymmetric synthesis of both natural products. The route first constructs another family member, streptazone B₁, using a rhodium-catalyzed distal selective allene-ynamide Pauson–Khand reaction. A regio- and enantioselective epoxidation under chiral phase-transfer catalytic conditions directly afforded streptazone A in 8 steps overall. In one additional step, a chemoselective, iridium-catalyzed reduction of the enaminone system then gave abikoviromycin. The reactivity of streptazone A towards a cysteine mimic, N-acetylcysteamine, was studied and revealed unanticipated transformations, including bis-thiol conjugation which may proceed via formation of a cyclopentadienone intermediate. With flexible access to these compounds, studies aimed to identify their direct biological targets are now possible.

Full text of DOI:10.1002/anie.202101439

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Communications
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How to cite: Angew. Chem. Int. Ed. 2021, 60, 10521–10525
International Edition: doi.org/10.1002/anie.202101439
German Edition: doi.org/10.1002/ange.202101439
Asymmetric Catalysis
Hot Paper
Concise Asymmetric Syntheses of Streptazone A and
Abikoviromycin**
Gustav J. Wørmer, Nikolaj L. Villadsen, Peter Nørby, and Thomas B. Poulsen*
Abstract: Streptazone A and abikoviromycin are alkaloids
that both feature an unusual arrangement of reactive function-
alities within a compact tricyclic ring system. Here, we report
a highly concise asymmetric synthesis of both natural products.
The route first constructs another family member, streptazo-
ne B1, using a rhodium-catalyzed distal selective allene-yna-
mide Pauson–Khand reaction. A regio- and enantioselective
epoxidation under chiral phase-transfer catalytic conditions
directly afforded streptazone A in 8 steps overall. In one
additional step, a chemoselective, iridium-catalyzed reduction
of the enaminone system then gave abikoviromycin. The
reactivity of streptazone A towards a cysteine mimic, N-
acetylcysteamine, was studied and revealed unanticipated
transformations, including bis-thiol conjugation which may
proceed via formation of a cyclopentadienone intermediate.
With flexible access to these compounds, studies aimed to
identify their direct biological targets are now possible.
N
atural products that feature unusual constellations of
reactive chemical groups are fascinating outcomes of micro-
bial biosynthesis and may constitute unique opportunities for
discovering interesting biological activity.[1] The strepta-
zones[2,3] (Figure 1A) are members of a larger family of
piperidine alkaloids with diverse biological activity[4–11] shar-
ing an interesting [4.3.0] bicyclic core (Figure 1A,B). In this
family, streptazolin 3[4,11a] has been the subject of sustained
interest from several laboratories due to the challenging
tricyclic urethane core structure.[12] We, however, have taken
special interest in streptazone A (1) which is reported to be
a potent inhibitor of liver cancer cell growth (HepG2, GI50
=
< 0.1 mM)[2] and features the unique constellation of an
enaminone, a Michael acceptor, and a bis-allylic epoxide
(Figure 1A). We were intrigued by the compact nature of the
multiple electrophilic sites embedded in this small molecule
(MW= 177 gmolÀ1) as well as the absence of information
about direct biological targets. Here, we report the first
asymmetric synthesis of (+)-streptazone A (1) in 8 steps, the
assignment of its absolute configuration, and the discovery of
conditions for selectively transforming 1 into abikoviromycin
(4)[10] in a single operation. Finally, we uncover an unantici-
Figure 1. A) Chemical structures of streptazones and a graphic repre-
sentation of antibonding molecular orbitals of streptazone A.
B) Related [4.3.0] natural products.
pated spectrum of thiol-reactivity inherent within the strep-
tazone A ring system.
In contrast to the plethora of syntheses of 3, no synthesis
has been reported for any epoxide-containing member of the
family.[12] It has been proposed that an epoxide facilitates the
formation of the [4.3.0] core by a ring-opening event during
the biosynthesis of streptazone E[13] and the camporidines[9]
(Figure 2A), however, the subsequent events that, for exam-
ple, result in re-closure/re-installation of the epoxide, are not
known in detail. Arguably, any synthetic strategies targeting
this functionality are likely to be challenging due to the
expected tendency for carbocation formation as a result of the
[*] G. J. Wørmer, Dr. N. L. Villadsen, Dr. P. Nørby, Prof. Dr. T. B. Poulsen
Department of Chemistry, Aarhus University
Langelandsgade 140, 8000 Aarhus C (Denmark)
E-mail: thpou@chem.au.dk
[**] A previous version of this manuscript has been deposited on
a preprint server (https://doi.org/10.26434/chemrxiv.13293356.v1).
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202101439.
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streptazolin (3) and streptazolone (Figure 1B, Figure 2B) and
found the intramolecular oxazolidinone Pauson–Khand
cycloaddition utilized by Mukai and co-workers[12e] appealing,
however, not directly applicable to our purpose. Instead, we
envisioned that the olefin could be positioned advantageously
by a distal selective intramolecular allene-ynamide Pauson–
Khand cyclization (Figure 2C), which, interestingly, is unpre-
cedented in the literature for [4.3.0] scaffolds. Following
ynamide and Crabbꢀ disconnections, the analysis converged
to commercial but-3-yn-1-amine hydrochloride 6 as an
optimal starting material (Figure 2C).
The synthesis was initiated using the Crabbꢀ homologa-
tion[14] of 6 to deliver 7 in 76% yield in multigram quantities
over two steps (Scheme 1). Next, we turned our attention to
establish the carbamate N–C(sp) bond. Several methodolo-
gies were evaluated[15] which generally failed to provide
reproducible results for a scalable synthesis. Initial attempts
based on TMS-bromoacetylene employing copper-catalyzed
ynamide formation delivered the allene-ynamide 8a in < 1%
yield, whereas the TIPS-bromoacetylene and the TES-
bromoacetylene, resulting in 8b and 8c, respectively, per-
formed significantly better after optimization (see the Sup-
porting Information).[16] The intramolecular allene-ynamide
Pauson–Khand cyclization was initially tested on all three
ynamides (8a–8c) using [Rh(CO)2Cl]2 for regioselectively
favoring the distal p-bond of the allene in the cyclization.[17–19]
Furthermore, for safe handling of CO gas, we studied the
reaction utilizing
a two-chamber system developed by
Skrydstrup and co-workers (see the Supporting Informa-
tion).[20] Indeed, we found that the cyclization worked on all
three substrates which establishes ynamides as functional
precursors for rhodium-catalyzed Pauson–Khand cyclization
to deliver [4.3.0] scaffolds. To our knowledge, only catalytic
molybdenum has previously been employed in an intra-
molecular allene-ynamide cyclization, although to access
[3.3.0] scaffolds.[21] In our hands, 8c was balanced appropri-
ately for both ynamide accessibility and performance in the
early cyclization attempts. After evaluation of several distal
selective catalysts (Scheme 1, step d), we found [Rh(CO)Cl-
(dppp)]2 suitable for a scalable synthesis. With rapid access to
the [4.3.0] core, installation of the C8-ethylidene group was
achieved by LiHMDS and acetaldehyde treatment to afford
a mixture (60:40 dr) of b-hydroxy ketones in 74% yield. The
diastereoisomers could readily undergo dehydration[22] using
Burgess reagent to predominantly afford syn-eliminated a,b-
unsaturated ketones 11 in 82% yield as a 55:45 cis/trans
mixture thereby allowing us to ultimately access the afore-
mentioned uncharacterized geometric isomers. To our
delight, protodesilylation and N-Boc deprotection could be
achieved simultaneously using diluted TFA which upon basic
work-up delivered streptazone B1 (2) and streptazone B2 (2’)
in combined 89% yield. Progressing forward, 2 and 2’ were
separated by standard chromatography to study the direct
epoxidation. Significant work was conducted in this particular
transformation to probe the overall reactivity of the tris-
olefins in 2/2’ (see the Supporting Information). Generally, we
found that electrophilic epoxidations using m-CPBA, DMDO
etc. under different conditions delivered complex mixtures,
presumably as a direct consequence of the more nucleophilic
Figure 2. A) [4.3.0]-assembly during the biosynthesis of streptazone E
and camporidine A and B. B) Different prior strategies towards strepta-
zolin and streptazolone. C) Retrosynthetic analysis involving sequential
transformations of three natural products.
double allylic tertiary position at C4 (Figure 1A) which we
speculate accounts for the severe instabilities reported for
4.[10c] Mindful of the expected challenges associated with the
epoxide, we pursued a strategy that would install this group at
the final stages. Indeed, we realized the potential for
developing an intriguingly direct approach in which strepta-
zone B1 (2) could be converted first to 1 and then further to 4
through sequential selective epoxidation and reduction (Fig-
ure 2C). However, based on the reported 13C NMR chemical
shifts of 22, the selective C3–C4 epoxidation was hard to
predict and methodologies describing the subsequent enam-
inone-reduction were absent in the literature. Access to 2
would be possible via the simplified [4.3.0] bicyclic core 5 that
was revealed by disconnecting the ethylidene sidechain
(Figure 2C).
This approach would also enable access to streptazone B2
(2’) which is defined by (E)-configuration at the C8–C9-olefin
(Figure 1A) and provide a path towards the (E)-isomers of
streptazone A and abikoviromycin—compounds currently
uncharacterized from natural sources. To develop an efficient
route to 5, we judiciously evaluated the prior syntheses of
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Scheme 1. Synthesis of streptazone A and abikoviromycin. CCDC 2059610 for (+)-1-ferrocenenoyl.
enaminone system. Next, we tested Jacobsenꢁs manganese-
based system[23] (Scheme 1, step h, entry 1), which allowed us
to identify 1 but unfortunately, the methodology failed to
deliver improvement after substantial experimentation and
was furthermore limited by irreproducible results on scales
greater than 0.05 mmol. To our delight, we found that
Shibasakiꢁs lanthanum-BINOL system[24] (Scheme 1, step h,
entry 2) also delivered 1, although as a racemic mixture. Upon
rational exclusion of each component in the system, it was
clear that lanthanum was irrelevant for the epoxidation, while
cumene hydroperoxide (CHP) at elevated temperature
sluggishly could deliver 1 regioselectively. With catalytic
DBU, we started to obtain promising results (Scheme 1, step
h, entry 3) and conversion of 2 was further improved using
TBAI as phase-transfer catalyst (PTC), although 1 was still
only formed in small amounts (Scheme 1, step h, entry 4).
This prompted us to investigate cinchona-based PTCs.[25]
Gratifyingly, the yield of 2 increased significantly and
stereoinduction was also obtained (Scheme 1, step h, entries 5
and 6). After further optimization (see the Supporting
Information) we found that the commercial catalyst 12
could deliver 1 in 62% yield with 72% ee (> 99% ee after
recrystallization). Subsequent derivatization of (+)-1 with
ferrocene-COCl enabled us to determine the absolute
configuration of (+)-1 by X-ray crystallography. Streptazo-
ne B2 (2’) could be converted to 1’ with equal efficiency.
The direct conversion from a free cyclic enaminone to the
corresponding conjugated imine is to our knowledge not
precedent in the literature. The transformation is complicated
by several factors: 1) multiple sites in 1 are prone to alternate
reductions, 2) facile over-reduction upon generation of the
conjugated imine, 3) 4 is reportedly highly unstable.[10c] We
decided to engage in a screen for reductive conditions
utilizing the unnatural (Z)-olefin (1’) under the assumption
that the overall outcome would be representative also for 1.
Our initial effort was based on the hypothesis that enami-
nones have increased electron density at the carbonyl group
which should render the system more susceptible for O-
activation. When 1’ was subjected to Tf2O, we indeed
observed O-triflation which was immediately subjected to
reductive conditions under palladium catalysis (Scheme 1,
step i, entries 1 and 2),[26,27] however, only decomposition of
the starting material was observed. Next, we tested method-
ologies reported for secondary amide reduction (Scheme 1,
step i, entries 3 and 4)[28,29] with neither indication of imine
nor amine formation. Moreover, we evaluated the possibility
of a 4-step sequence by initial copper hydride-catalyzed 1,4-
reduction of the enaminone, triflation, reduction and lastly
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*
À
relying on the reported enzymatic reoxidation to 4 by SF-
973B oxidoreductase.[30–32] This idea, however, fell short of the
goal already in the initial 1,4-reduction (Scheme 1, step i,
entries 5 and 6). Finally, inspired by the recently reported
total synthesis of herquline B and C by Baran and co-workers
employing the iridium-diethylsilane system for amide reduc-
tions developed by Cheng and Brookhart, we found the
conditions applicable to directly deliver the imine product 4’
(Scheme 1, step i, entry 7) (see the Supporting Information
for evaluation of reductions).[33,34] In the case of 1, the
reduction proceeded slower but nonetheless afforded 4 in
43% overall best yield, (see the Supporting Information for
general stability of 4). In the case of 1’, simply increasing the
reaction time pushed the reaction toward the dihydro adduct,
whereas 1 required additional reductant to deliver dihydroa-
bikoviromycin (see the Supporting Information), another
[4.3.0] natural product.[6,35] Hence, the system may be
employed to afford both the imine- and the amine [4.3.0]
bicyclic classes by careful reaction control.
Finally, we investigated the electrophilic properties of
1 towards a biological thiol mimetic, N-acetylcysteamine, at
physiological pH (Figure 3A). Near complete conversion of
1 (95% by HPLC, Figure 3B) was obtained after 24 h thereby
confirming the intrinsic reactivity of 1 towards thiols.
Surprisingly, we were able to identify three major thiol-
conjugates by analytical RP-HPLC, which we successfully
isolated with the major product 14 corresponding to epoxide
opening delivering a single diastereoisomer (Figure 3A,B).
The epoxide was curiously opened at the tertiary position,
not the secondary, and opening had occurred with inversion of
configuration. We speculate that this reactivity is a direct
consequence of the double allylic contribution to the s C O
bond that in turn favors the tertiary carbon for incoming thiol-
nucleophiles. In accord, crystallization of the natural product
À
revealed that this particular C O bond was slightly elongated
(Figure 3C). The remaining two products from the conjuga-
tion reaction corresponded to a set of diastereoisomers (15/
16) and were unmistakably the products of double addition of
N-acetylcysteamine (Figure 3A,B). Again, we were surprised
by the behavior of 1, as it became evident from HMBC
couplings, that 15/16 resulted from a completely different
reaction path. We hypothesize that initial 1,4-addition induces
epoxide opening, via the corresponding enolate, thereby
unmasking a highly reactive cyclopentadienone electrophile
(likely stabilized by the fused amine)[36] that undergoes
a subsequent nucleophilic addition at the a-position and
ultimately results in dehydration (Figure 3D). To gain
mechanistic insight, we conducted the conjugation in D2O/
CD3CN and found that C6 had undergone full deuterium
exchange, which could not be attributed to tautomerization of
1 nor was this observed for 14, thereby suggesting that a-
addition principally may be viewed as a 1,6-addition. To our
knowledge, this is the first evidence supporting a masked
cyclopentadienone natural product electrophile.
From a biological perspective, this data supports that 1 can
act as a cysteine-reactive natural product and potentially also
with the ability to facilitate cross-linking.[37] We anticipate that
this highly peculiar reactivity will manifest itself in biological
studies of this natural product family. Attempts to reproduce
the reported toxicity against HepG2 cells were, in our hands,
not successful with 1 (or 1’). These observations, along with
the observed intrinsic reactivity of 1, underscores the
importance of mapping the cellular targets of 1.
In summary, we have developed the first syntheses of
streptazone B1/B2, streptazone A, abikoviromycin and dihy-
droabikoviromycin in 7, 8, and 9 steps, respectively. The route
also afforded access to geometric double-bond isomers of
streptazone A and abikoviromycin, that may constitute
members of this natural product family that are yet to be
isolated. We discovered a new intramolecular Pauson–Khand
cycloaddition performed on an allene-tethered ynamide
substrate to deliver a bicyclo[4.3.0] core. Furthermore, we
present a highly regioselective epoxidation employing chiral
phase-transfer catalysis to epoxidize streptazone B1 to A. This
in turn enabled the direct reduction of the cyclic enaminone
functionality using iridium catalysis to access abikoviromycin
and dihydroabikoviromycin. Finally, we demonstrate that
streptazone A possesses several electrophilic sites by in vitro
thiol-conjugation studies which include formation of surpris-
ing double thiol-adducts that presumably are the result of
a cyclopentadienone intermediate.
Acknowledgements
This work was supported by grants from the Novo Nordisk
Foundation (grant NNF19OC0054782 to T.B.P.) and the
Carlsberg Foundation (grant CF17-0800 to T.B.P.). We further
thank the K. A. Jørgensen lab for access to chiral stationary
phase UPC2 and Anders Bodholt Nielsen and Dennis Wilkens
Figure 3. Studies of thiol-conjugation to streptazone A reveals dichoto-
mous reactivity. CCDC 2059611 for (+/À)-1.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · electrophile ·
natural products · total synthesis · transition metal catalysis
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Manuscript received: January 29, 2021
Accepted manuscript online: February 11, 2021
Version of record online: March 18, 2021
Angew. Chem. Int. Ed. 2021, 60, 10521 –10525
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