Synthesis of Swinhoeisterol A, Dankasterone A and B, and Periconiastone A by Radical Framework Reconstruction

Article abstract of DOI:10.1021/jacs.9b12899

A switchable radical framework reconstruction approach to structurally unique 13(14 → 8),14(8 → 7)diabeo-steroid swinhoeisterol A was developed. The conversion of an ergostane skeleton proceeded through the intermediacy of a 13(14 → 8)abeo-framework as pr

Full text of DOI:10.1021/jacs.9b12899

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Communication
Synthesis of Swinhoeisterol A, Dankasterone A and B, and
Periconiastone A by Radical Framework Reconstruction
Fenja L. Duecker, Robert C. Heinze, and Philipp Heretsch
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b12899 • Publication Date (Web): 23 Dec 2019
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Synthesis of Swinhoeisterol A, Dankasterone A and B, and
Periconiastone A by Radical Framework Reconstruction
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Fenja L. Duecker, Robert C. Heinze, Philipp Heretsch*
Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustraße 3, 14195 Berlin, Germany
Supporting Information Placeholder
β scission of an alkoxide, followed by further addition and
ABSTRACT: A switchable radical framework reconstruction
elimination steps.
approach to structurally unique 13(14→8),14(8→7)diabeo-steroid
swinhoeisterol A was developed. The conversion of an ergostane
skeleton proceeded through the intermediacy of a 13(14→8)abeo-
framework as present in the dankasterone and periconiastone
family of natural products and features a β scission of a 14-alkoxy
radical with concomitant generation of the C8−C13 bond. From
this intermediate, and dependent on the conditions employed, the
cascade continues with a Dowd–Beckwith rearrangement and leads
to the formation of the 13(14→8),14(8→7)diabeo-framework of
the swinhoeisterol class of natural products. The synthesis of these
frameworks then allowed for efficient access to swinhoeisterol A
(1), dankasterone A (Δ4-2), dankasterone B (2), and periconiastone
A (3).
Understanding the biogenesis of natural products provides the
synthetic organic chemist with inspiration and benchmark when
designing and executing a laboratory synthesis.[1] Within this
respect, the abeo-steroids, a class of steroid-derived compounds
that exhibit one or more C‒C bond migrations, still hold much
ambiguity. Whether the formation of abeo-steroids from the
classical steroid backbone involves multiple steps and enzymes or
a rearrangement cascade, typically remains speculative in the
absence of biosynthetic intermediates from the producing
organism. Quite frequently, polar reactions and pathways are then
evoked to account for C‒C bond breaking and migratory events
while radical alternatives are rarely brought forward.[2,3]
However, radical cyclization events were recently shown to
competently allow for diverse framework manipulations in our
syntheses of 15(14→22)abeo-steroid strophasterol A[4] and
11(9→7)abeo-steroid pleurocin A/matsutakone.[5] In continuation,
and to collect more such reactivity evidence for potential radical
alternatives in abeo-steroid biosynthesis, we now set out our search
for processes in which a cascade of radical rearrangements
profoundly alters the steroid framework. With this in mind, the
swinhoeisterol class of natural products[6‒8] with its unprecedented
6/6/5/7 ring system presented itself as target and a yet unmet
synthetic challenge.[9] These marine metabolites were first isolated
and structurally elucidated in 2014 from the sponge Theonella
swinhoei endemic to the South China Sea.[6] Swinhoeisterol A–F
vary in their degree of oxidation with swinhoeisterol A (1, Figure
1) and E (not shown) possessing the lowest oxidation level of the
class.[6‒8] Biological activity has been reported with cytotoxicity
toward A549 and MG-63 cells. Furthermore, a polar biogenesis
proposal was put forward consisting of the oxidative cleavage of
the C8−C14 bond in a steroid precursor, an aldol step, as well as a
Figure 1. Structures of swinhoeisterol A (1), dankasterone B (2),
and periconiastone A (3) and their formal origin.
Formally, the steroidal descent of the swinhoeisterols can be
revealed by two migratory events (Figure 1), i.e. (1) cleavage of the
C13−C14 bond in a steroid A and reconnection of C13 to C8 to
furnish B, and (2) cleavage of the C8−C14 bond in B and
reconnection of C14 to C7 to yield C. The intriguing structure of
intermediate B was found in a small collection of natural
products[10] with the dankasterones[10a,b] being the most prevalent
examples. Dankasterone A (Δ4-2) was isolated in 1999 from the
Halichondria sponge-derived fungus Gymnascella dankaliensis
endemic to the Sea of Japan,[10a] while dankasterone B (2) was
isolated in 2007 and has the lowest oxidation level of this class.[10b]
Thus, also a certain geographical proximity between the respective
grounds of isolation of these and the former natural products is
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evident. Cytotoxic activities in murine P388 as well as human
confirmed the formation of two 13(14→8)abeo-ergostanes 7 and 8
as minor products of the reaction (for X-ray crystallographic data,
see Supporting Information), wherein 8 is the 7-iodo derivative of
7. Furthermore, 9 was isolated as the main product comprising the
desired 13(14→8),14(8→7)diabeo-skeleton but with an additional
degree of unsaturation (compared to L). Another minor product
observed was 15-iodo derivative 10, which, as 8, was obtained as a
single diastereomer. With this result closely following our initial
hypothesis, we aimed at identifying conditions to both improve
cancer cell lines CT26 and K562 have been reported.[11] Very
recently, periconiastone A (3) was isolated from cultures of the
endophytic fungus Periconia sp. TJ403-rc01 and showed
significant antibacterial properties against MRSA (4 µg/mL).[12] Its
13(14→8)abeo-4,14-cyclo-system D was interpreted to derive
from dankasterone B (2).[13]
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8
We now envisioned the radical cascade shown in Scheme 1A to
translate the formal framework reconstruction into a chemical
access to all three families of natural products from one precursor.
A 14-hydroxy steroid enone of type E could thus undergo alkoxy
radical initiated β scission of the C13−C14 bond (F→G), followed
by attack of the so-generated C13 centered radical to the enone to
give α-keto radical H.[14] Radical H would act as a hub for
accessing either (and selectively) the dankasterone and
periconiastone or the swinhoeisterol class of natural products. The
former would derive from radical quench of H to give the
13(14→8)abeo-framework I. Down this line, Danieli reported a
rearrangement of crustecdysone (4) to the 13(14→8)abeo-product
5 under UV-irradiation (Scheme 1B).[15a] If H remains unquenched
and is persistent for long enough, the cascade could continue via a
Dowd–Beckwith rearrangement,[16] consisting of an attack of said
α-keto radical to the adjacent oxo functionality to furnish a second
tertiary alkoxy radical J. This intermediate could undergo another
β scission of the cyclopropane and give tertiary radical K.
Abstraction of an H atom then furnishes the ene dione system L
possessing the desired 13(14→8),14(8→7)diabeo-structure.
yield and selectivity of the cascade. Exposing
6
to
(diacetoxyiodo)benzene and iodine in benzene[18] led to complete
conversion of the starting material after only 30 minutes at 25 °C
and furnished 8 as the only isolable product in 76% yield (entry 2).
Using the same reagents but more forcing conditions only led to
complex mixtures and diabeo-products were never observed. On
the other hand, selective generation of 9 was achieved when using
mercuric oxide and iodine instead (68% of 9, only trace amounts of
8, entry 3).[19]
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Table 1. Radical Framework Rearrangement of 14-
Hydroxy Steroid 6
Scheme 1. A. Mechanistic rationale of proposed radical
rearrangement leading to the dankasterone or swinhoeisterol
frameworks; B. Danieli’s rearrangement of crustecdysone
(4).[15]
isolated yields
#
reagentsa
7
8
9
10
b
1
2
3
Pb(OAc)4, I2
15%
8%
76%
<5%
52%
n.o.
68%
10%
n.o.
n.o.
PhI(OAc)2, I2 n.o.
HgO, I2 n.o.
a
b
Conditions: C6H6, 0.025 M. CaCO3 was added; n.o.: not
observed.
We were now in a position to access selectively key
intermediates to synthesize dankasterone and periconiastone as
well as swinhoeisterol. Thus, spiro-compound 8 was de-iodinated
using dissolving metal conditions (Zn, NH4Cl)[20] to furnish 7
(Scheme 2A). Opening of the i-steroid whilst retaining the oxo
functionality at C6 was achieved applying strong Brønsted acid
(H2SO4 in HOAc)[21] and immediate saponification of the so-
obtained mixture of partly acetylated 11 gave the desired 5β-isomer
in 80% yield (d.r. 19:1, β/α) over 2 steps. Oxidation of the 3-
hydroxy group using Dess–Martin periodinane completed an
efficient synthesis of dankasterone B (2) in 9 steps and 22% total
yield from ergosterol. All analytical data matched reported data,
furthermore, single-crystal X-ray diffraction analysis allowed for
an unequivocal confirmation of the originally assigned structure of
2 (see Supporting Information). From this natural product,
dankasterone A and periconiastone A could be reached in one step.
Thus, Saegusa‒Ito oxidation [Pd(OAc)2] of a mixture of silyl enol
Following this plan, we chose our previously described 14-
hydroxy steroid 6,[4] which we obtained from ergosterol (not
shown) in 4 steps and 42% overall yield, to explore several options
for the generation of the 14-alkoxy radical. When treating 6 with
Pb(OAc)4 and I2 under CaCO3-buffered conditions in refluxing
benzene,[17] we obtained a complex mixture containing four major
products 7–10 (Table 1, entry 1). Careful separation and analysis
ethers obtained from
2 by treatment with KHMDS and
TMSCl/Et3N gave dankasterone A (Δ4-2, 36% yield) together with
recovered dankasterone B (2, 62%). On the other hand, when
treating 2 with DBU in toluene, intramolecular aldol addition
between C4 and C14 occurred and resulted in the formation of
periconiastone A (3) as a single diastereomer in 86% yield. This
supported the original biosynthetic hypothesis and suggests
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dankasterone B (2) to be the precursor of 3. Furthermore, the easy
Protonation during workup took place selectively from the β-face.
Controlled ozonolysis of the Δ22 bond then gave an aldehyde,
which was successfully merged with sulfone 22 to yield exclusively
the (Z)-olefin 14 in 63% yield over 2 steps.[23]
access to periconiastone A (10 steps, 19% total yield from
ergosterol) puts us in a position to investigate the biological
properties of this structurally unique antibiotic agent.
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9
For the synthesis of swinhoeisterol A (1) we employed
rearrangement product 9, being aware that the ergostane-derived
stereoconfiguration of remote C24 was inverse to the one in the
natural product and, thus, had to be adjusted.[22] Ozonolytic
cleavage of steroid side-chains and Julia‒Kocienski olefination of
so-obtained aldehydes with sulfones of type 22 (Scheme 2B) have
been reported.[23] The dense functionality of 9 as well as of several
down-stream intermediates, though, required careful consideration
and probing for the right opportunity, if tedious redox- or protecting
group operations were to be minimized. The required sulfone 22[23]
was accessible through standard transformations starting from (R)-
Roche ester (19), shortening a previously reported sequence to
Under a variety of conditions, we tried to effect hydrogenation
of the (22Z)-double bond, but only at elevated hydrogen-pressure
and with Pd or Pt catalysts reduction occured, which was in all
cases accompanied by extensive epimerization of C24 (for Pd/C up
to 50% epimerization, for Pt/C 25%, see Supporting Information).
Since radical methods for hydrogenation also failed,[26] we
circumvented this problem via a hydroboration/oxidation-
defunctionalization sequence. Thus, hydroboration (giving
predominantly 23-OH, as judged by NMR), accompanied by
desired reduction of the 14-oxo moiety, oxidative workup,
acetonide protection of the 6,14-diol, and eventually, Barton–
McCombie reaction, furnished 15 with the desired saturated side
chain and no epimerization. Applying acidic conditions (BF3•OEt2,
HOAc) then led to the cleavage of the acetonide under
concommitant i-steroid opening.[27] Removal of the 3-acetyl group
in thus-obtained material using non-basic conditions (DIBAl‒H) to
prevent re-formation of the i-steroid was followed by oxidation of
the 3- and 14-hydroxy groups and furnished a dione, of which the
Δ5 bond could now readily be isomerized with DBU to provide
enone 16. All that remained was installation of the 4-exo-methylene
motif under concomitant generation of the 5α-stereoconfiguration.
Initially, we explored reductive alkylation protocols. However, this
option had soon to be abandoned since the desired 4-
(hydroxymethylated) 3-oxo derivative could only be obtained in
low and irreproducible yield owing to a high propensity to undergo
retro-aldol reaction.[28]
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tosylate 21[24] via diol 20[25]
.
Attempted Julia‒Kocienski olefination on most down-stream
intermediate-derived aldehydes revealed mainly aldol reactivity, an
intramolecular process between readily enolizable C7 and the C22
aldehyde (see Supporting Information). Interestingly, and likely
attributed to less favourable conformation, C7 was less prone to
engage in such aldol reactions, when the i-steroid was still present.
Thus, to remove some reactive sites of the diene dione system 9, a
1,6-reduction with L-selectride was employed to deliver the desired
Δ8 bond and furnish enolate 12. The lability of the latter towards
oxygen required immediate reduction in the same pot (LiAlH4) and
gave hydroxy ketone 13. The enolate in the former intermediate
was thus preventing further reduction by masking the 14-oxo
moiety, which also inhibited isomerization of the Δ8 bond.
Scheme 2. A. Synthesis of Dankasterone A (Δ4-2) and B (2), and Periconiastone A (3). B. Synthesis of Swinhoeisterol A (1).a
a See Supporting Information for reagents and conditions; AIBN = 2,2ʹ-azobisisobutyronitrile, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene,
DIBAl‒H = diisobutylaluminum hydride, DMAP = 4-(dimethylamino)pyridine, DMP = Dess–Martin periodinane, HMDS = 1,1,1,3,3,3-
hexamethyldisilazide, mCPBA
=
3-chloroperbenzoic acid, Ms
=
methanesulfonyl, PT
=
1-phenyl-1H-tetrazol-5-yl,
Tf =
trifluoromethanesulfonyl, TMS = trimethylsilyl, Ts = 4-methylbenzenesulfonyl.
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Instead, we aimed for a Nishiyama‒Stork radical cyclization[29]
,
and, towards this reaction, selectively reduced enone 16 (NaBH4,
CeCl3, complete diastereocontrol for the 3β-isomer) and
functionalized the thus-obtained allylic alcohol with
(chloromethyl)chlorodimethylsilane. Finkelstein reaction provided
necessary iodide 17 and set the stage for cyclization onto the 4-
position, for which a protocol employing catalytic quantities of
tinhydride (AIBN, nBu3SnCl, NaBH3CN)[30] was crucial for
success. The resulting dimethyl oxasilolane (not shown) was
directly converted to diol 18 applying Tamao’s conditions.[31]
Eventually, treatment of 18 with Tf2O and DBU effected
elimination of the primary alcohol and furnished swinhoeisterol A
(1) in 21 steps and 1% overall yield starting from ergosterol. Also,
we were able to obtain 24-epi-swinhoeisterol (24-epi-1) in 16 steps
and 3% overall yield for future biological comparison. In this case,
(22E)-configurated compound 6 was reduced with H2, Pt/C (5%
epimerization), suggesting a pronounced influence of both, the
configuration of Δ22 as well as the carbon backbone on the outcome
of hydrogenation (see Supporting Information).
separations, and to Prof. Dr. Dieter Lentz for X-ray
crystallographic analyses (Freie Universität Berlin).
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In summary, we here describe a switchable and divergent
approach to abeo-steroids swinhoeisterol A (1), dankasterone A
(Δ4-2) and B (2), and periconiastone A (3) through radical
framework reconstruction. The choice of reagents for alkoxy
radical generation allows an intermediate radical to function as a
hub of the whole sequence and lead either to the dankasterone,
periconiastone or swinhoeisterol class of natural products. Ongoing
work in our laboratory focusses on a synthetic access to the
remaining members of each class and studies to reveal the
biological target of novel and potent anti-MRSA agent
periconiastone A.
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2015), isolation and structural assignment of further three swinhoeisterols
was reported. These were then named swinhoeisterol C, D, and E.
Reference [6] neither cites this patent nor does it adhere to this
nomenclature.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/jacs.XXX.
General methods; detailed experimental studies; experimental
procedures and spectral data; comparison of synthetic and natural
swinhoeisterol A, of synthetic and natural dankasterone A and B,
and of synthetic and natural periconiastone A; H and 13C NMR
1
spectra; X-ray crystallographic data; and references (PDF)
X-ray crystallographic data for 2 (CIF) 1900563
X-ray crystallographic data for 8 (CIF) 1900562
AUTHOR INFORMATION
Corresponding Author
*philipp.heretsch@fu-berlin.de
ORCID
Fenja L. Duecker: 0000-0002-1060-9309
Robert C. Heinze: 0000-0002-3431-816X
Philipp Heretsch: 0000-0002-9967-3541
(11) T.-H. Lee, C.-C. Chen, J.-J. Chen, H.-F. Liao, H.-S. Chang, P.-J.
Sung, M.-H. Tseng, S.-Y. Wang, H.-H. Ko, Y.-H. Kuo, New and Cytotoxic
Components from Antrodia camphorata. Molecules 2014, 19, 21378–
21385.
Notes
(12) W. Gao, C. Chai, Y. He, F. Li, X. Hao, F. Cao, L. Gu, J. Liu, Z. Hu,
The authors declare no competing financial interests.
Y. Zhang, Periconiastone A, an Antibacterial Ergosterol with a
Pentacyclo[8.7.0.01,5.02,14.010,15]heptadecane System from Periconia sp.
TJ403-rc01. Org. Lett. 2019, 21, 8469–8472.
ACKNOWLEDGMENT
(13) The authors of reference [12] do not indentify 2 as dankasterone B
and do not cite its seminal isolation report (reference [10b]).
Financial support for this work was provided by Deutsche
Forschungsgemeinschaft (grant no. HE 7133/7-1), the Boehringer
Ingelheim Stiftung (exploration grant to P.H.) and Studienstiftung
des Deutschen Volkes (Ph.D. scholarship to R.C.H.). We
acknowledge the assistance of the Core Facility BioSupraMol
supported by the DFG. We are grateful to Mira Mueller for
experimental assistance, to Christiane Groneberg for HPLC
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