Pharmacophore-Directed Retrosynthesis Applied to Rameswaralide: Synthesis and Bioactivity of Sinularia Natural Product Tricyclic Cores

Article abstract of DOI:10.1021/acs.orglett.9b02713

A pharmacophore-directed retrosynthesis strategy applied to rameswaralide provided simplified precursors bearing the common 5,5,6 (red) and 5,5,7 (blue) skeleton present in several cembranoid and norcembranoids from Sinularia soft corals. Key steps include a Diels-Alder lactonization organocascade delivering the common 5,5,6 core and a subsequent ring expansion affording a 5,5,7 core serviceable for the synthesis of rameswaralide. Initial structure-activity relationships of intermediates en route to the natural product have revealed interesting differential and selective cytotoxicity.

Full text of DOI:10.1021/acs.orglett.9b02713

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Pharmacophore-Directed Retrosynthesis Applied to Rameswaralide:
Synthesis and Bioactivity of Sinularia Natural Product Tricyclic Cores
†
‡
†
‡
,†
Nathanyal J. Truax, Safiat Ayinde, Khoi Van, Jun O. Liu, and Daniel Romo*
†
Department of Chemistry & Biochemistry, Baylor University, Waco, Texas 76710, United States
‡
Department of Pharmacology and Molecular Sciences, John Hopkins School of Medicine, 725 North Wolfe Street, Baltimore,
Maryland 21205, United States
*
S Supporting Information
ABSTRACT: A pharmacophore-directed retrosynthesis strat-
egy applied to rameswaralide provided simplified precursors
bearing the common 5,5,6 (red) and 5,5,7 (blue) skeleton
present in several cembranoid and norcembranoids from
Sinularia soft corals. Key steps include a Diels−Alder
lactonization organocascade delivering the common 5,5,6
core and a subsequent ring expansion affording a 5,5,7 core
serviceable for the synthesis of rameswaralide. Initial
structure−activity relationships of intermediates en route to
the natural product have revealed interesting differential and selective cytotoxicity.
oft corals belonging to the genus Sinularia produce a
number of cembranoid and norcembranoid diterpenes
bearing a complex, caged, highly oxygenated tri- or tetracyclic
the established absolute stereochemistry of a probable
3,9
S
biosynthetic precursor. While several groups have pursued
1
0−14
the synthesis of rameswaralide (6)
(5),
and ineleganolide
1
5−21
skeleton as seen in several representative members 1−6
which bear the 5,5,7 core (blue, Figure 1), to our
1
−6
(
Figure 1). However, the limited availability of these natural
knowledge, there are no reported total syntheses. Less
synthetic work has been directed to members possessing the
5
,5,6 core (red) such as that found in yonarolide, scabrolides,
22−25
dissectolides, and sinulochmodin C (1−4).
Our interest in ineleganolide (5) and rameswaralide (6)
stems from their structural complexity and the lack of
information regarding structure−activity relationships (SAR)
for these diterpenoids. Toward the latter goal, herein we apply
our recently disclosed pharmacophore-directed retrosynthesis
26
(
PDR) strategy to enable simultaneous collection of SAR for
rameswaralide and congeners en route to a total synthesis. An
initial hypothesis to guide our PDR approach is premised on
the noted similarities in the common 5,5,7-core (blue, Figure
1
) which we propose may encompass the pharmacophore of
ineleganolide (5) and rameswaralide (6). Variations in these
core structures derive from points of attachment of the fused 6-
membered D ring to the C rings and a bridging ether in
ineleganolide derived from a presumed oxa-Michael addition.
Furthermore, sinulochmodin C (4) and scabrolides A and B
9
Figure 1. Structurally related, polycyclic Sinularia diterpenoid natural
products.
(
2) are constitutional isomers of ineleganolide (5), yet in the
cell lines tested, they have shown moderate to no
bioactivity.
products from corals has hindered a broader understanding of
their bioactivity. To date, moderate cytotoxicity of inelegano-
27,28
We propose that the 5,5,7 core structure
5
imparts the greatest bioactivity to this class of diterpenoids. We
therefore devised a retrosynthesis that would allow access to
the 5,5,7 core through a ring expansion proceeding via a 5,5,6
core intermediate. This strategy would enable a systematic
lide (5) toward the P388 leukemia cell line (11.6 μM ED )
5
0
7
was reported. The potential anti-inflammatory activity and
cytotoxicity toward A549 human lung carcinoma epithelial
8
cells (IC50 67 ± 3.7 μM) of rameswaralide (6) was also
8
reported. Furthermore, with the exception of rameswaralide,
the absolute stereochemistry of these diterpenoids has not yet
Received: August 1, 2019
been confirmed; however, it was indirectly assigned based on
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02713
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
study of the impact of core ring size and location of attachment
of the D-ring to the 5,5,7-core on bioactivity. Thus, annulation
of various D-rings to these core structures and attendant
functionality would provide valuable SAR information en route
to members of this family. It is certainly possible that in these
highly functionalized caged natural products the entire
molecule is required for bioactivity; nevertheless, application
of PDR facilitates and opens the possibility of identifying
equipotent, simplified derivatives as well as potential new
bioactivities not previously observed within this class of
diterpenoids.
this same enone was recently obtained by Liang and co-
23
workers through a different synthetic strategy. Extensive
optimization to identify acid scavenging conditions that did
not interfere with the DAL process ultimately led to
replacement of the previously reported biphasic proton shuttle
2
9,30
base system
with only Hunig’s base (i-Pr NEt). These
̈
2
conditions reliably provided the desired tertiary alcohol 8 in
77% yield with high diastereoselectivity (>19:1, H NMR). An
1
optimized route to obtain enone 15 was also identified
involving direct workup with 1 M HCl. The relative
stereochemistry of this product was confirmed by X-ray
crystallography (Scheme 2, inset). While the current route
provides racemic material, our previous studies suggest the
potential for an asymmetric variant of the key DAL
We decided to set rameswaralide (6) as our initial target
since it displays some of the most compelling bioactivity in this
6
class of tetracyclic diterpenoids (Scheme 1). Based on
29,30
process.
Scheme 1. Pharmacophore-Directed Retrosynthetic
Approach toward Rameswaralide
Scheme 2. Synthesis of Diene 9 and the 5,5,6 Tricyclic
Cores 8 and 15 via the Diels−Alder Lactonization
Organocascade
10
11
previous work by both Mehta and Trost, who independ-
ently synthesized a similar 5,5,7 core of rameswaralide, we
anticipated that annulation of the D-ring would be challenging
given the lack of further efforts toward this end. With this in
mind, we proposed that α-halo enones such as enone 7 could
serve as highly versatile intermediates for several D-ring
annulation strategies toward rameswaralide (6). The α-bromo
enone 7 could be accessed via a cyclopropanation ring
expansion strategy from 5,5,6 tricycle 8. Early access to both
tricyclic intermediates 7 and 8 provides a divergence point
toward several members of this natural product family and
would enable a systematic study of potential variations in
bioactivity between 5,5,6 and 5,5,7 cores. We envisioned access
to tricycle 8 through our recently described Diels−Alder
lactonization (DAL) organocascade process of diene 9 and
Enol ether 8 is a regioisomer of an ideal alkene substrate for
the planned ring expansion to the desired cycloheptanone ring.
This realization coupled with the propensity for elimination of
the tertiary alcohol leading to enone 15, under even mild acidic
conditions, led us to consider strategies for direct transposition
of the alkene through an electrophilic addition/alkene
transposition pathway. Davies reported a similar alkene
transposition utilizing N-bromosuccinimide (NBS) presumably
29,30
35
acryloyl chloride.
Diene 9 is available through a Stille
driven by release of strain. Indeed, the desired transposition
cross-coupling and 1,2 addition to cyclopentenone 10, in turn
available through a known Piancatelli rearrangement of
furfuryl alcohol (11).
of the less stable ring-fused alkene was achieved under mild
conditions with NBS to provide the brominated, regioisomeric
enol ether 16.
31
Our synthetic studies began with the preparation of diol 9
With an initial substrate for cyclopropanation in hand, we
studied the Furukawa-modified, Simmons−Smith cyclopropa-
32−34
employing known iodide 12.
The latter was subjected to a
36−38
Stille coupling with ethoxy vinyl stannane 13 to afford racemic
diene 14. Subsequent 1,2 addition with MeLi proceeded with
high diastereoselectivity (>19:1 dr) and deprotection provided
diol 9 in 45% yield over two steps. With the requisite diene in
hand, we attempted the key DAL reaction initially employing
racemic benzotetramisole; however, typical DAL conditions
provided only enone 15 corresponding to the core of
yonarolide (1). This product presumably results from
elimination of the tertiary alcohol catalyzed by trace HCl;
nation (Scheme 3).
However, not surprisingly, treatment
of alcohol 16 to cyclopropanation conditions initially generates
the tertiary alkoxide which cyclized to epoxide 21 as the sole
product. Unfortunately, the instability of epoxide 21 precluded
its use as a cyclopropanation substrate. Protection of the
tertiary alcohol as a triethylsilyl (TES) ether 17 precluded
epoxide formation; however, the cyclopropanation still did not
proceed and only starting material was recovered. We
considered that the tertiary bromide may be preventing
B
DOI: 10.1021/acs.orglett.9b02713
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Alkene Transposition of Enol Ether 8 and a
Complex-Induced, Proximity Effect Driven
Cyclopropanation
FeCl conditions reported by Seagusa for cyclopropyl TMS
3
38
ethers, no reaction was observed. Use of ceric ammonium
46,47
nitrate (CAN) with NaI,
which presumably generates
iodine radicals, led to cleavage of the cyclopropane providing
primary iodide 22, which proved to be highly unstable. This
suggests that the ethyl ether is not being oxidized directly, but
rather iodine radical is formed and attacks the least hindered
48
carbon of the cyclopropane as proposed in Scheme 4.
To direct the cyclopropane ring expansion, we targeted the
monobromocyclopropane 24 (Scheme 5). We anticipated that
Scheme 5. Synthesis of Bromocyclopropane 24 and Ring
Expansions to Functionalized 5,5,7 Tricyclic Ring Systems
approach of the Zn-carbenoid to the more accessible convex
face. Therefore, standard radical dehalogenation conditions
provided enol ether 18. However, attempted cyclopropanation
again led only to recovered starting material. We next
considered removal of the TES protecting group which,
based on models, may be forcing the ethyl group of the enol
ether into the more accessible convex face through a gearing
effect. The net result would be steric blocking of both faces of
the enol ether. Furthermore, deprotection of the alcohol would
enable a complex-induced proximity effect through formation
of a pendant carbenoid proximal to the enol ether, thereby
increasing the rate of cyclopropanation through intramolecu-
3
9,40
larity.
Use of allylic alcohols in this manner through
directed Furukawa-modified, Simmons−Smith cyclopropana-
41−45
tion is precedented.
Indeed, after removal of the TES
the bromide would enable ring expansion via an ionic
mechanism or, alternatively, it could block addition of a
radical to the undesired cyclopropyl carbon. The same
cyclopropanation conditions employed previously were
performed with tribromomethane and led to a very sluggish
conversion to the desired cyclopropane. The presence of
oxygen has been reported to increase the rate of cyclo-
propanation by aiding in the formation of the bromozinc
protecting group, enol ether 19 participated in the desired
cyclopropanation employing diiodomethane to deliver cyclo-
1
propane 20 as a single diastereomer (>19:1 by H NMR) in
3
8% yield (unoptimized), sufficient for our initial studies of the
ring expansion. The relative stereochemistry was confirmed by
X-ray analysis and verifies that methylene transfer occurred
exclusively on the sterically less accessible, concave face and
that delivery of the zinc carbenoid is likely directed by the
ideally situated, in situ generated tertiary alkoxide.
49,50
carbenoid.
Thus, addition of a balloon of O after alkoxide
2
formation and addition of tribromomethane greatly enhanced
the reaction rate and led to reproducible yields of cyclopropane
With cyclopropane 20 in hand, we attempted radical
mediated, oxidative ring expansions (Scheme 4). Under
1
24 with high diastereoselectivity (>19:1, H NMR). The
relative stereochemistry of the cyclopropane ring was assigned
by analogy to cyclopropane 20 and coupling constant analysis
of the cyclopropane protons.
Scheme 4. Attempted Ring Expansion of Cyclopropane 20
We next attempted the ring expansion utilizing various silver
salts but were unsuccessful in obtaining the desired enone 27
(
Scheme 5) and instead obtained pyranone 25, derived from
ring expansion followed by oxa-Michael reaction, and enone 26
derived from elimination. Since an ionic mechanism failed, we
again turned to addition of a halo radical and, in particular, a
−
bromide radical through oxidation of Br with CAN. This
reaction afforded the desired ring-expanded product 28 along
with significant quantities of tribromide 29 (relative stereo-
chemistry assigned by X-ray; see the SI). The latter product
presumably results from the desired ring expansion followed by
α-bromination. While this α-bromination was not expected, it
proved extremely useful. Treatment of dibromo ketone 28
C
DOI: 10.1021/acs.orglett.9b02713
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Cell Viability Data (Alamar Blue Assay, 72 h Incubation) of Select Intermediates toward Sinularia Natural Products
a
8
b
c
Rameswaralide was previously assayed only against the A549 cell line (IC of 67 ± 3.7 μM). See the SI for synthetic details. Analogues 34−36,
5
0
52
were kindly provided by Prof. Brian Stoltz (Caltech).
under several basic conditions to give the α-bromo enone 7 led
to complex mixtures. However, treatment of tribromo ketone
surprisingly, the presence of α,β-enones on both the 5,5,6
and 5,5,7 core structures (i.e., 26, 30, 31) led to the greatest
cytotoxicity toward all cancer cell lines but with some
interesting and unexpected selectivities observed. A notable
example involves the most potent analogue tested, our key
synthetic intermediate α-bromo enone 30, which uniquely
displays nanomolar activity (0.39 ± 0.03 μM) against the
HCT116 cell line with 8−27X greater potency over other
cancer cell lines and primary HUVEC. In addition, the cross-
conjugated dienone 31 displays micromolar activity against
HCT116 cells (28.90 ± 6.36 μM) but is inactive up to 100 μM
toward other cancer cell lines tested, including primary
HUVEC. Furthermore, it appears that α,β-enones present in
the cyclopentane ring (C ring) do not inherently result in
cytotoxicity given that enone 15, possessing a β-disubstituted
enone, is inactive (up to 100 μM) toward all cell lines tested,
while dienone 31, possessing a β-monosubstituted cyclo-
hexanone, displays cytotoxicity toward HCT116 cells.
However, the tertiary alcohol in enone 33 appears to reduce
toxicity compared to dienone 31. Overall, it is interesting to
note that the 5,5,6-tricyclic cores are generally less cytotoxic to
all cell lines tested compared to the 5,5,7-variants (cf. dienones
31 and 26). However, the α,β-unsaturated lactones 35 and 36
display selective cytotoxicity toward MDA-MB-231 cells but
comparable cytotoxicity to HUVEC. The SAR gathered to date
provides preliminary validation for our initial hypothesis that
the 5,5,7-tricyclic core present in some of the most cytotoxic
members of this family may be important for activity.
However, further support for this hypothesis and the relevance
of the observed bioactivities to the natural products themselves
must await further studies including eventual proteomics
studies to identify cellular targets.
2
9 with DBU provides the epoxy, α-bromo enone 30 in which
the tertiary alkoxide again cyclizes to form an epoxide and
serves to prevent elimination of the tertiary alcohol.
Our described PDR strategy toward rameswaralide (6)
provided access to both 5,5,6- and 5,5,7-tricyclic intermediates,
bearing resemblance to Sinularia natural products, that were
assayed for bioactivity. Furthermore, intermediates 15 and 19
were readily transformed into three additional analogues 31−
3
3 to provide additional SAR data (see the SI for synthetic
51
details). In collaboration with Stoltz’s group, three additional
tricyclic analogues 34−36 were assayed to widen the SAR
profile.
5
2
Cell viability assays (alamar blue viability assay, 72 h
incubation) employing three cancer cell lines were performed
with the described simplified Sinularia natural product
derivatives (Table 1). Rameswaralide previously showed
cytotoxicity against the A549 (human lung epithelial
8
carcinoma) cell line with an IC50 of 67 ± 3.7 μM. We
therefore assayed this cell line along with triple-negative breast
cancer (MDA-MB-231) and colorectal carcinoma (HCT116)
cell lines along with primary human umbilical vein endothelial
cells (HUVEC) to obtain information regarding selective
cytotoxicity. The presence of α,β-enones, as a result of our
synthetic strategy and also present in some Sinularia family
members, opens the possibility of covalent modifying
compounds via thio-Michael additions. However, when
selectivity can be achieved with these Michael acceptors,
they have found utility for drug design and identification of
53
novel cellular targets.
While a complete SAR profile is not yet available, several
interesting observations can be made from initial assays
performed on the described tricyclic intermediates. Not
In summary, application of a PDR strategy that employed
the use of a Diels−Alder lactonization organocascade has
D
DOI: 10.1021/acs.orglett.9b02713
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Organic Letters
Letter
enabled rapid access to both 5,5,6 and 5,5,7 tricyclic cores
present in several Sinularia soft coral-derived natural products
including rameswaralide. Preliminary cytotoxicity studies
revealed some interesting cytotoxicities and selectivities that
will be further verified and elaborated upon throughout our
total synthesis efforts and subsequent in-depth biological
studies. We anticipate that the versatile intermediate, α-bromo
enone 30, will serve as a useful springboard toward several
members of the Sinularia class of natural products bearing the
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02713.
U. K.; Tuniki, V. R.; Kalivendi, S. V.; Bunce, R. A.; Yenamandra, V.
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(
CCDC 1937890−1937893 contain the supplementary crys-
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emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
Ring Systems in Plumarellide and Rameswaralide Using a
Coordinated Intramolecular Cycloaddition Approach, Based on a
Common Biosynthesis Model. Tetrahedron Lett. 2013, 54, 324−328.
*
E-mail:daniel_romo@baylor.edu.
(
15) Moeller, K. D. Intramolecular Anodic Olefin Coupling
ORCID
Reactions: Using Radical Cation Intermediates to Trigger New
Umpolung Reactions. Synlett 2009, 2009, 1208−1218.
Jun O. Liu: 0000-0003-3842-9841
Daniel Romo: 0000-0003-3805-092X
Notes
(16) Tang, F.; Moeller, K. D. Intramolecular Anodic Olefin
Coupling Reactions: The Effect of Polarization on Carbon-Carbon
Bond Formation. J. Am. Chem. Soc. 2007, 129, 12414−12415.
The authors declare no competing financial interest.
(17) Tang, F.; Moeller, K. D. Anodic Oxidations and Polarity:
Exploring the Chemistry of Olefinic Radical Cations. Tetrahedron
2009, 65, 10863−10875.
ACKNOWLEDGMENTS
■
Support from NIH NIGMS (R37 GM052964 and R37
GM052964S1 to D.R. and J.O.L. (subcontract)), FARI and
NCI (P30CA006973 to J.O.L.), and a Ruth L. Kirschstein
Predoctoral Fellowship (F31 GRANT12692796, to N.J.T) is
gratefully acknowledged. We thank Dr. Kevin Klausmeyer
(18) Horn, E. J.; Silverston, J. S.; Vanderwal, C. D. A Failed Late-
Stage Epimerization Thwarts an Approach to Ineleganolide. J. Org.
Chem. 2016, 81, 1819−1838.
(19) Roizen, J. L.; Jones, A. C.; Smith, R. C.; Virgil, S. C.; Stoltz, B.
M. Model Studies To Access the [6,7,5,5]-Core of Ineleganolide
Using Tandem Translactonization−Cope or Cyclopropanation−
Cope Rearrangements as Key Steps. J. Org. Chem. 2017, 82,
(
Baylor) for all X-ray analyses. We thank Prof. Brian Stoltz,
Nicholas Hafeman, Steven Loskot, Chris Reimann, and Beau
Pritchett (Caltech) for the warm collaboration leading to the
more complete preliminary SAR profile presented herein.
1
(
3051−13067.
20) Craig, R. A., II; Roizen, J. L.; Smith, R. C.; Jones, A. C.; Virgil,
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DOI: 10.1021/acs.orglett.9b02713
Org. Lett. XXXX, XXX, XXX−XXX