Collective Total Synthesis of Casbane Diterpenes: One Strategy, Multiple Targets

Article abstract of DOI:10.1002/anie.202015243

Of the more than 100 casbane diterpenes known to date, only the eponymous parent hydrocarbon casbene itself has ever been targeted by chemical synthesis. Outlined herein is a conceptually new approach that brings not a single but a variety of casbane deri

Full text of DOI:10.1002/anie.202015243

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Accepted Article
Title: Collective Total Synthesis of Casbane Diterpenes: One Strategy,
Multiple Targets
Authors: Alois Fürstner, Lorenz E. Löffler, and Conny Wirtz
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Collective Total Synthesis of Casbane Diterpenes: One Strategy, Multiple Targets
Lorenz E. Löffler, Conny Wirtz, and Alois Fürstner*
Abstract: Of the more than 100 casbane diterpenes known to date, only the eponymous parent
hydrocarbon casbene itself has ever been targeted by chemical synthesis. Outlined herein is a
conceptually new approach that brings not a single but a variety of casbane derivatives into reach,
especially the more highly oxygenated and arguably more relevant members of this family. The key
design elements are a catalyst controlled intramolecular cyclopropanation with or without subsequent
equilibration, chain extension of the resulting stereoisomeric cyclopropane building blocks via
chemoselective hydroboration/cross coupling, and the efficient closure of the strained macrobicyclic
framework by ring closing alkyne metathesis. Of arguably highest relevance is the fact that a hydroxy-
directed catalytic trans-hydrostannation allows for late-stage diversity. These virtues are manifested
in concise total syntheses of depressin, yuexiandajisu A, and ent-pekinenin C; the latter turned out to
be identical with euphorhylonal A, which had obviously been misassigned in the literature.
The bicyclo[12.1.0]pentadecane framework of the casbane diterpenes represents the formal
progenitor of the more complex polycyclic skeletons of the lathyrane, jatrophane, tigliane, daphnane
and ingenane families.1,2 Despite their role as a central node within this large biosynthetic network,
casbane derivatives themselves are rare: the flowering plants of the genus Euphorbia and the
biologically totally unrelated soft corals of the genus Sinularia are by far the major sources. From this
small number of producing organisms, however, more than 100 different structural variants have been
isolated to date, which feature a bewildering diversity of oxygenation patterns and stereochemical
permutations along the hydrocarbon rim.
*
L. E. Löffler, C. Wirtz, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
Email: fuerstner@kofo.mpg.de
Supporting Information and ORCID identification numbers of the authors of this article can be found under
#########
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Figure 1. Selection of naturally occurring casbane diterpenes
The few examples shown in Figure 1 are representative. Most naturally occurring casbane diterpenes
comprise a cis-disubstituted cyclopropane unit, which appears in both antipodal formats (compare the
depressin derivatives 2, 33 with the “pseudo-enantiomeric” compounds 6,4 75). The same is true for
the trans-cyclopropane series, as illustrated by 9 and 10, which are isomeric even though they derive
from the same soft coral.3 It is of note, however, that the absolute configuration of several casbanes
was either not addressed by the isolation teams or has only been inferred by plausibility arguments,
especially in the older literature. Another common structural variation concerns the oxygenation
pattern of the “northern” sector, in that the C5 methylene group is frequently oxidized to the alcohol
or ketone level, with or without concomitant oxygenation of the surrounding positions. Once again,
2
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the stereochemistry is evidently not uniform as the comparison of 126 and 137 suggests, which
supposedly have opposite configurations at C5 (in other cases such as 4,8 the configuration of this
center is simply unknown). Moreover, the parent C18 methyl substituent can be transformed to the
alcohol (11)6, aldehyde (4,8 12,6 137) or carboxylic acid level (e. g. yuexiandajisu A, which is either 14 or
ent-14).9 Additional diversity is gained by isomerization (8,10 137), (partial) saturation (9)3 and/or
epoxidation (5)11 of the trisubstituted alkenes and/or by additional oxygenation of the “lower” sector
of the constituent framework.12
The fact that casbane diterpenes were evolved by sessile marine sponges and, in parallel, by higher
plants is fascinating and suggestive at the same time. In this context, it is worth remembering that
Euphorbia plants (the “spurge” family) are commonly considered toxic; some of them play important
roles in traditional Chinese medicine (“Lang Du”) for the treatment of various ailments.13 In line with
this notion, pekinenin C (12) was shown to cause cell cycle arrest in the G0/G1 phase and apoptotic
cell death via the mitochondrial as well as the death-receptor pathways.14 Equally noteworthy is the
role of certain casbanes as phytoalexins: while the amount of 1 in seedlings of the castor bean (Rhicinus
communis) is minute,15 exposure to certain fungi massively upregulates its biosynthesis as part of the
plant’s defense mechanism.16,17 Along the same lines, ent-10-oxodepressin (7) as a prototype member
of the “enantiomeric” series was recognized as phytoalexins of rice.5 This report also marks a rare case
of a casbane derivative isolated from a higher plant not belonging to the Euphorbia genus; in view of
the importance of rice for the sustention of humankind, the discovery of the potential fungicidal
properties of 7 is arguably relevant and warrants further scrutiny.
The increasing awareness of the possible biological roles of the casbane diterpenes is not yet reflected
in advanced synthetic studies. So far, the eponymous hydrocarbon 1 is the only member that has been
targeted in the past: five independent chemical syntheses and an enzymatic approach were published
prior to the turn of the millenium;18,19,20,21,22,23 all activity seems to have ceased since then. Although a
detailed analysis of this prior art is beyond the scope of this Communication, it is noteworthy that all
approaches – except for the enzymatic route23  struggled with the macrocyclization step, which was
low yielding in most cases. What is more, either the ring closure itself or the necessary functional group
manipulations in its aftermath invariably led to isomer mixtures that required tedious separation. Any
new foray must address these issues; most importantly, positional and/or configurational double bond
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isomerism should be strictly avoided. Since the known chemical syntheses gave racemic 1 unless the
“chiral pool” was tapped (cis-chrysanthemic acid, (+)-2-carene),24 it is also appropriate and timely to
envisage an catalytic enantioselective route. In recognition of the fact that some of the oxygenated
casbane derivatives are of larger biological significance than the parent compound itself, a high level
of synthetic flexibility is also deemed necessary; from the conceptual viewpoint, any (late-stage)
diversity as integral part of the synthesis blueprint would mark a notable strategic advance.25,26,27
Scheme 1. “Diversity-oriented” retrosynthetic analysis
We conjectured that the trans-hydrometalation of internal alkynes, which has recently become a focal
point of research in our laboratory,28 provides valuable opportunities in this context (Scheme 1).
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Specifically, treatment of propargyl alcohols with R3EH (E = Si, Ge, Sn) in the presence of [Cp*RuCl]4
as catalyst follows a stereochemically unorthodox trans-addition mode and delivers the R3E- group
with high fidelity to the proximal C-atom of the former triple bond. This outcome is mechanistically
well understood; in essence, it originates from the cooperativity between the unprotected –OH group
of the substrate and the polarized [RuCl] unit of the catalyst.29 When applied to a cycloalkyne of type
F, the resulting alkenylstannane (germane, silane) G should allow either a methyl-, a hydroxymethyl, a
formyl-, or a carboxyl group to be stitched to the C-4 position of the casbane framework where such
variation is common (see above). Since the directing C5-OH group can either be kept as such or be
oxidized to the corresponding ketone (or even be removed), all basic oxygenation patterns in the
“northern” sector should be accessible from a single platform. Cycloalkyne F, in turn, might be forged
by ring closing alkyne metathesis (RCAM):30,31,32 since the best available catalysts activate triple bonds
exclusively while leaving all sorts of double bonds untouched, the integrity of the trisubstituted alkenes
punctuating the carbon skeleton of F seems guaranteed. The same, however, cannot be taken for
granted for the cyclopropyl group: any alkyne metathesis catalyst is a Schrock alkylidyne, which is
nucleophilic at carbon.33 This inherent polarization might entail (reversible) ring opening and/or
decomposition, especially if forcing conditions are needed (see the Insert in Scheme 1): this is likely to
be the case in the projected application given the strain of the resulting 14-membered ring F that
incorporates two E-configured alkenes as well as the linear alkyne; the annelated cyclopropyl ring
rigidifies the skeleton even further. Therefore an application to the casbane series will also clarify an
as yet unknown aspect of alkyne metathesis chemistry in general. Further analysis reveals that the
building block C can be used twice en route to F, which reduces the synthetic exertion and helps render
the route practical. The cyclopropyl fragment B can be traced back to lactone A, which is available by
rhodium catalyzed intramolecular cyclopropanation:34,35 since this step proceeds under catalyst
control and the elaboration of A into B can be performed with or without epimerization of a derived
aldehyde intermediate, all possible isomers are accessible. The blueprint shown in Scheme 1 hence
combines flexibility at the outset with late-stage diversity and should therefore bring a considerable
number of casbane derivatives into reach.
In the forward sense, diazoester 15 was prepared by a literature route from prenyl alcohol and
diketene followed by diazo transfer (Scheme 2); its treatment with catalytic Rh2(S-MEPY)4 furnished
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multigram amounts of 16 with high optical purity (93% ee).34,35 After reduction of the lactone with
DibalH in CH2Cl2 at low temperature, the resulting crude lactol was subjected to Wittig olefination to
give alcohol 17,36 which was then oxidized to the corresponding aldehyde 18. It is at this point that the
synthesis route bifurcates for the first time: when 18 was subjected to regular Corey/Fuchs
alkynyation37 and C-methylation under optimized conditions,38 the cis-configured enyne 19 was
obtained. Stirring of a solution of 18 in MeOH with K2CO3, however, causes equilibration with
formation of the thermodynamically more stable trans-isomer and hence opens access to the epimeric
trans-configured building block 20 (dr  9:1).39 The somewhat modest yields of 19 and 20 solely reflect
the high volatility of these hydrocarbons. The enantiomeric compounds are obviously equally well
accessible.40
Scheme 2. a) NaOAc, THF, reflux, 70%; b) (i) p-acetamidobenzenesulfonyl azide, Et3N, MeCN; (ii) LiOH,
H2O, 75%; c) [Rh2(5S-MEPY)4](MeCN)2 (0.6 mol%), CH2Cl2, reflux, 87%, 93% ee; d) Dibal-H, CH2Cl2,
78°C; e) Ph3P=CH2, THF, 0°CRT, 55% (over both steps); f) DMP, CH2Cl2, 0°CRT; g) CBr4, PPh3,
CH2Cl2, 0°C; h) nBuLi, Et2O/DMPU, then MeI, 78°CRT, 51% (19, over three steps), (20, 63%, over
four steps, cis:trans = 1:9); i) K2CO3, MeOH, 50°C
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Scheme 3. a) (i) nBuLi, THF, 78°C30°C; (ii) (PhMe2Si)2Cu(CN)Li2, 78°C, 90%; b) nBuLi, PhMe2SiCl,
THF, 30°CRT, quant.; c) [(PPh3)2NiCl2] (8 mol%), MeMgBr, toluene, reflux, 91%; d) I2, PPh3,
imidazole, CH2Cl2, 0°CRT, 93%; e) Dess-Martin periodinane, CH2Cl2, 0°CRT; f) MeCCMgBr, THF,
0°C, 78% (over both steps); g) TBDPSCl, imidazole, CH2Cl2/DMF, 84%; h) NIS, 2,6-lutidine, HFIP, CH2Cl2,
20°C, 89%; i) (i) 25, Zn, LiCl, TMSCl, 1,2-diodoethane, THF; (ii) Pd(PPh3)4 (6 mol%), 82%; j) TBAF, THF,
0°CRT, 84%; k) NIS, HFIP, 0°C, 73% (dr = 42:58); l) NIS, HFIP, HOAc, 0°C, 70%; HFIP =
hexafluoroisopropanol, NIS = N-iodosuccinimide; TBAF = tetra-n-butylammonium fluoride; TBDPS =
tert-butyldiphenylsilyl
Fragment 24 to be used twice during the synthesis was readily obtained on treatment of the lithium
salt of 3-pentyn-1-ol (21) with the cyanocuprate derived from PhMe2SiLi and CuCN (Scheme 3).41
Alternatively, this very same product can be made from 2,3-dihydrofuran 22 by metalation/silylation
followed by nickel catalyzed opening of the resulting compound 23 with MeMgBr.42 Whereas the first
method works well on a 3 g scale and takes a single step, the two-step procedure is more practical
when it comes to making much larger quantities. Oxidation of 24 to the corresponding aldehyde
followed by addition of propynylmagnesium bromide gave 26. Although it would be fairly
straightforward to set this propargyl alcohol center in isomerically pure form,43 no effort in this
direction was undertaken at this stage: in view of the uncertainty concerning the configurational
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assignment of the C5-OH group in various casbane derivatives, access to both isomers was probably
necessary anyway. Compound 26 was then O-silylated prior to iododesilylation on reaction with NIS in
CH2Cl2 at 20°C in the presence of hexafluoroisopropanol (HFIP) and 2,6-lutidine following a procedure
developed by Zakarian and coworkers.44 Under these conditions, the yield of alkenyl iodide 27 was high
and no sign of double bond isomerization was observed within the limits of detection (E:Z  95:5, 1H
NMR). This product was then subjected to a palladium catalyzed Negishi coupling45 with the organozinc
reagent derived from iodide 25,46 which also derives from 24. Somewhat unexpectedly, however, the
iododesilylation of the resulting product 28 did not proceed well under the conditions that had worked
so smoothly for the shorter building block 26;44 several alternative methods were also tried but equally
found low-yielding, erratic, or unselective.47 Since (inseparable) isomer mixtures need to be strictly
avoided for the sake of practicality, considerable optimization was necessary at this stage. Part of the
problem is the poor solubility of 28 in the polar medium comprised of HFIP as (co)solvent. Therefore
we considered the cleavage of the TBDPS-ether prior to iododesilylation, even though this order of the
events bears risk and has hardly any precedent:48 upon addition of an [I+] source to the resulting
polyunsaturated substrate 29, the unprotected OH group might interfere by attacking any transient
iodonium ion and thus entail iodoetherification. This was indeed observed when the reaction was
carried out with NIS in HFIP: the cyclic ether 30 was formed as a mixture of two diastereomers. Addition
of HOAc,49 however, allowed the problem to be solved and the desired product 31 to be obtained in
1
well reproducible 70% yield with impeccable integrity of the double-bond geometry (E:Z  95:5, H
NMR). Although the generality of this finding needs yet to be explored in detail, it suggests that these
modified Zakarian conditions might further increase the scope of iododesilylation and render the
reaction applicable to otherwise “protecting group free” synthetic ventures.
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Scheme 4. a) 9-H-9-BBN, THF, 0°CRT; b) 31, [(dppf)PdCl2] 10 mol%), Ba(OH)28H2O, 69%; c) 37 (20
mol%), 38 (22 mol%), MS 5Å, toluene, reflux, 60% (34+35); d) [Cp*RuCl]4 (2.5 mol%), Bu3SnH, CH2Cl2,
88% (36); e) MeI, Pd(PPh3)4 (5 mol%), [Bu4N][Ph2PO2], CuTC, DMF, 67%; f) MnO2, CH2Cl2, 73%; g) MeLi,
THF, then DMF, 78°CRT, 68% (4), 53% (5-epi-4); 9-BBN = 9-borobicyclo[3.3.1]nonane, Cp* =
pentamethylcyclopentadienyl; CuTC = copper thiophene-2-carboxylate
Figure 2. Structure of 34 in the solid state (casbane numbering scheme)
The coupling of the building blocks commenced with an exquisitely chemoselective hydroboration of
the terminal alkene in 19 in the presence of the internal alkyne, which was achieved on treatment with
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9-H-9-BBN dimer in THF; the choice of solvent is critical (Scheme 4).50,51 The resulting alkylborane 32
was then subjected to a Suzuki coupling52 with alkenyl iodide 31 using Ba(OH)28H2O as promotor;53,54
other bases gave inferior results. Since the latest generations of alkyne metathesis catalysts endowed
with (chelating) silanolate ligands work even in the presence of unprotected alcohols despite the
inherent nucleophilicity/basicity of the operative Schrock-type alkylidyne unit,55,56 diyne 33 thus
formed could be directly subjected to RCAM to give the cycloalkynes 34 and 35. The fact that the
reaction had to be carried out in refluxing toluene is tentatively ascribed to the high ring strain of these
compounds; this aspect and the rather forcing conditions notwithstanding, the cyclopropyl unit
survived. At this stage, the two diastereomeric alcohols were easily separated by flash chromatography
and the structure of 34 in the solid state was confirmed (Figure 2). It shows that the cis-configuration
of the three-membered ring is intact: neither cleavage nor scrambling had interfered during the
metathesis of the adjacent triple bond.
With 34 and 35 in hand and the configuration of the C5-OH group rigorously established, the project
reached the phase of late-stage diversification. To this end, 35 was subjected to ruthenium catalyzed
trans-hydrostannation to give product 36 as the only detectable isomer in good yield.29,57 A formal Stille
cross coupling with MeI under conditions previously developed in our laboratory allowed the yet
missing methyl substituent to be introduced,58,59 before the resulting product was oxidized to the
corresponding ketone 2. The NMR spectra as well as the specific rotation of synthetic 2 are in excellent
agreement with those of depressin reported in the literature.3 We hence confirm the constitution and
absolute configuration assigned to this natural product derived from the soft coral Sinularia depressa
collected off the shore of Hainan Province, China.60
Next, stannane 36 was transformed into the corresponding aldehyde 4 upon treatment with MeLi (2
equiv.) followed by quenching of the resulting organolithium species with DMF.61 Compound 4 could
represent euphorhylonal A, a natural product extracted from Euphorbia hylonoma; the spectra of 4,
however, were not matching. Since the configuration of euphorhylonal A at C5 had not been
established by the isolation team and is therefore an obvious point of concern,8 the epimeric
cycloalkyne 34 was subjected to an analogous sequence of trans-hydrostannation/formylation. Yet,
the recorded spectra of the resulting aldehyde 5-epi-4 were not in accord with the literature either. It
was hence clear that euphorhylonal A does not contain a cis-configured cyclopropane as proposed in
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the literature;8 unfortunately, the published data do not provide any hint as to which of the two
positions on the three-membered ring might have been misassigned and needs to be inverted.8
Scheme 5. a) 20, 9-H-9-BBN, THF, 0°CRT; b) 31, [(dppf)PdCl2] 5 mol%), Ba(OH)28H2O, 82%; b) 37 (20
mol%), 38 (22 mol%), MS 5Å, toluene, reflux, 76% (40+41); c) [Cp*RuCl]4 (2.5 mol%), Bu3SnH, CH2Cl2,
65% (42) + 12% (isomer, see SI),62 74% (43); d) MeLi, THF, then DMF, 78°CRT, 61% (ent-12), 69%
(44); e) MeLi, THF, then CO2, 78°CRT, 51%
Since we had planned a foray into the trans-series anyway in order to showcase the flexibility of the
synthesis blueprint, pekinenin C (12)6 isolated from the roots of Euphorbia pekinensis was the obvious
target because it differs from nominal eyphorhylonal A (4) solely in the configuration of one center on
the cyclopropane ring. This compound exhibits appreciable cytotoxicity rooted in its ability to induce
apoptotic cell death.14 The synthesis follows the established route in that the appropriate enyne 20
(see Scheme 2) was subjected to chemoselective hydroboration followed by cross coupling of the
resulting alkylborane with 31 to give diyne 39 in readiness for RCAM (Scheme 5). Using the same
catalyst generated in situ from complex 37 and ligand 38,55 the macrocyclization proceeded within
minutes at 70°C; the comparison with the cyclization of diyne 33, which had required reflux
temperature, suggests that the trans-configured cyclopropane imposes less strain on the transition
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state and the resulting bicyclic scaffold of 40 and 41. That the three-membered ring remained intact
during the alkyne metathesis reaction echoes the results discussed above. Once again, the
diasteromeric alcohols could be easily separated at this stage; the configuration of the C5-OH was
determined by Mosher ester analysis (see the SI). Each isomer was then subjected to trans-
hydrostannation and subsequent formylation to give isomers ent-12 and 44, respectively.62
Gratifyingly, the spectral data as well as the specific rotation of synthetic ent-12 correspond well to
those of euphorhylonal A;8 the NMR spectrum is also identical with that of pekinenin C, whereas the
sign of the []D is opposite.6 We hence conclude that euphorhylonal A and pekinenin C are not
diastereomeric but almost certainly enantiomeric to each other.63 This finding shows that
phylogenetically closely related Euphorbia plants can produce antipodal secondary metabolites.
Finally, 42 was carboxylated by tin/lithium exchange followed by a CO2 quench; the resulting acid ent-
14 represents naturally occurring (+)-yuexiandajisu A and clarifies the previously unknown absolute
configuration of this secondary metabolite with antibacterial properties derived from the medical
plant Euphorbia ebracteolata; the roots of this plant are one of the ingredients of the traditional
Chinese medicine recipe “Lang du”.9
In summary, we have developed a short, efficient, selective, modular and inherently flexible approach
to the casbane family of diterpenes, as illustrated by the total synthesis of depressin, yuexiandajisu A
and ent-pekinenin C; the latter proved identical with natural euphorhylonal A which had obviously
been misassigned by the isolation team. The chosen route also clarifies a previously unknown aspect
of alkyne metathesis in that it proves that a cyclopropane ring conjugated to the triple bond to be
activated and catalytically transformed remains intact even under forcing conditions. Finally, the
present study further illustrates the virtues of directed trans-hydrometalation, a reaction manifold that
had been largely unknown until recently but proves versatile and enabling, not least as an entry point
into a variety of stereodefined trisubstituted alkenes.28,59,60a,64 Further studies along these lines,
including approaches to even more complex target compounds, are underway and will be reported in
due course.
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Acknowledgements
Generous financial support by the MPG is gratefully acknowledged. We thank Dr. J. Novacek, who had
explored a different approach to the casbane diterpenes, Dr. K. Yahata for discussion, and all analytical
departments of our Institute for excellent support, especially Mr. J. Rust and Prof. C. W. Lehmann for
solving the X-ray structure of compound 34.
For the Table of Contents
A cornucopia: Sessile soft corals as well as certain higher plants produce a multitude of casbane
diterpenes of greatly different oxygenation patterns. A new synthetic approach to this family of natural
products was designed that allows a large subset to be encompassed, yet is short, efficient and
selective. Key to success was a combination of catalytic cyclopropanation, alkyne metathesis and trans-
hydrometalation chemistry.
Keywords: alkyne metathesis  cyclopropanes  terpenes  macrocycles  trans-addition
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Small amounts of protodestannylated products were observed under these conditions, cf.
Supporting Information.
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Only in the hydrostannation of 40, a noticeable amount of the corresponding alpha,cis-isomer
was formed in addition to the alpha,trans-adduct 42 for reasons that are currently unclear; for
details, see the Supporting Information.
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Pekinenin C is reported to have an [α]2D5 = 19 (c 0.04, CHCl3), whereas euphorhylonal A shows
an [α]2D5 = +90.5 (c 0.30, CHCl3); for synthetic ent-12 we recorded [α]D20 = +77.3 (c 0.11, CHCl3),
[α]2D5 = +74.5 (c 0.11, CHCl3). The difference between the two supposedly enantiomeric natural
products cannot be explained without access to authentic extracts; we note, however, that the
sample of pekinenin C used to determine the rotatory power was very dilute.
a) H. Sommer, A. Fürstner, Chem. Eur. J. 2017, 23, 558-562; b) H. Sommer, A. Fürstner, Org. Lett.
2016, 18, 3210-3213.
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