Total Synthesis of (±)-Leonuketal

Article abstract of DOI:10.1021/acs.orglett.0c03364

Leonuketal is an 8,9-seco-labdane terpenoid with a unique tetracyclic structure, owing to a diversity-generating biosynthetic C-C bond cleavage event. The first total synthesis of leonuketal is reported, featuring a Ti(III)-mediated reductive cyclization of an epoxy nitrile ether, an unusual ring-opening alkyne formation as part of an auxiliary ring strategy, and the previously undescribed Au(I)-catalyzed cyclization of a β-keto(enol)lactone to assemble the core spiroketal motif.

Full text of DOI:10.1021/acs.orglett.0c03364

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Total Synthesis of ( )-Leonuketal
Phillip S. Grant, Daniel P. Furkert,* and Margaret A. Brimble*
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ABSTRACT: Leonuketal is an 8,9-seco-labdane terpenoid with a unique tetracyclic structure, owing to a
diversity-generating biosynthetic C−C bond cleavage event. The first total synthesis of leonuketal is
reported, featuring a Ti(III)-mediated reductive cyclization of an epoxy nitrile ether, an unusual ring-
opening alkyne formation as part of an auxiliary ring strategy, and the previously undescribed Au(I)-
catalyzed cyclization of a β-keto(enol)lactone to assemble the core spiroketal motif.
yclization and oxidation processes are recognized as the
Cprincipal drivers of complexity generation in the
biosynthesis of terpenoid natural products.1−9 However, a
third mode of complexity generation involving the cleavage of a
C−C bond is operative in the biogenesis of seco-terpenoids
(Figure 1A).10 Such processes lead to increased chemical
diversity in a cluster of related secondary metabolites by
alteration of the parent carbon skeleton. Moreover, C−C bond
cleavage is typically oxidative, and reactions facilitated by the
increase in oxidation statesuch as ketalization or aldol
processeslead to further skeletal rearrangement.
Efficient synthesis of the alkyne-substituted cyclohexanol
ring of 9 appeared to pose a challenge. While related
cyclohexanols have been assembled from geraniol derivatives,
we aimed to identify a method to efficiently incorporate the
requisite alkynyl moiety.36−44 To this end, we developed an
auxiliary ring strategy wherein bicyclic ketone 11 was used as a
synthetic linchpin for the construction of monocyclic alkyne 9
(Figures 1D and 2A). Bicyclic ketone 11 could, in turn, be
disconnected to epoxide 12, a derivative of geraniol, by a
Ti(III)-mediated radical cyclization.
Our synthesis thus began with treatment of epoxide 12 with
in situ generated Cp2TiCl2, efficiently affording bicyclic ketone
13 after acidic hydrolysis (Scheme 1).45−49 This trans-
formation, while proceeding in modest yield (32%), scaled
up easily (6.5 g) and afforded reliable access to diastereomeri-
cally pure ketone 13.50 Preliminary investigations revealed that
the complementary cyclization employing epoxide 14
terminating with intermolecular addition to acetonitrilewas
found to be capricious and low yielding (Figure 2B).51
Next, epimerization of the C7 alcohol of 13 was achieved by
an oxidation−reduction sequence, first requiring protection of
the C4 ketone. Following ketal protection, the C7 alcohol was
oxidized with DMP, then reduced with L-selectrideaffording
desired epimer 11 after ketal deprotection. Attempts to effect
alcohol epimerization on more advanced intermediates 16 and
17 in exploratory studies, which would have circumvented the
necessary ketone protection−deprotection steps, returned
either unreacted starting material or the undesired epimer
(Figure 2; see the SI for details).
Leonuketal (1) is a tetracyclic 8,9-seco-labdane terpenoid
marked by high stereochemical and architectural complexity
chiefly owing to a C−C bond cleavage event in its biosynthesis
(Figure 1B).11 Peng and co-workers isolated 1 from Chinese
liverwort (Leonurus japonicus) in 2015 and reported significant
vasorelaxant activity (EC50 = 2.32 μM) against KCl-induced
contraction of rat aorta.11 Leonuketal (1) and other seco-
labdanes such as saudin (2), pallambin A (3), and pallamolide
B (4) exemplify the structural complexity enabled by
biosynthetic C−C bond cleavage (Figure 1B).12,13 This
characteristicalongside important bioactivitieshas ren-
dered seco-labdanes attractive synthetic targets and useful
platforms for the development of synthetic methods.14−33
Previously, we reported the synthesis of the bridged
oxabicyclic core of leonuketal (1), as lactone 5, by an efficient
Diels−Alder reductive-cyclization sequence (Figure 1C).34
This strategy relied on a proposed epimerization of the C3
carbon for advancement of 5 to 1; however, a comprehensive
screen of bases failed to identify conditions for the planned
transformation.
Our revised retrosynthetic strategy was targeted toward late
stage spiroketal 7, which we recognized would provide access
to 1 by incorporation of the C3 hydroxybutanone chain and
elaboration of the lactone moiety (Figure 1D). We planned to
assemble the spirocyclic core of 7 by Au-mediated cyclization
of alkyne 8, which could be accessed from iodide 9 through
appendage of the lactone moiety by alkylation.35
Received: October 8, 2020
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© XXXX American Chemical Society
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auxiliary ring, encouraging equatorial approach of L-selectride
and preventing ring-flipping of the ketone.
With alcohol 11 in hand, attention was turned to cleavage of
the auxiliary pyran ring and formation of the requisite alkyne
motif. Both transformations were simultaneously achieved by
exploitation of an unusual Shapiro-type fragmentation
reaction.52 To this end, 11 was converted to an intermediate
tosyl hydrazone, which was subsequently treated with methyl
lithium, resulting in formation of alkyne 18 in 89% yield over
two steps.53 This process likely proceeded via generation of
vinyl lithium 20, which subsequently underwent β-elimination.
This sequence enabled the synthesis of 18 in 7 steps on gram-
scale.
Our auxiliary ring strategy parallels the synthesis of seco-
terpenoids in general, wherein ring-deconstruction is leveraged
as an enabling (bio)synthetic tool. The value of this sequence
is underscored by an abundance terpenoids sharing the
dimethylcyclohexanol substructure of 18; indeed, a structure
search revealed >14 000 natural products containing this
motif.54
With scalable access to alkyne 18 secured, focus was placed
on construction of the caged spiroketal core of leonuketal (1).
To this end, the iodide derived from 21 was synthesized over 3
steps by hydroxymethylation of 18, followed by mesylation and
iodination. The subsequent alkylation of the iodide required
some investigation. Initially, we examined the Frater−Seebach
alkylation with β-hydroxyesters, which generally resulted in
decomposition of the nucleophile, returning starting materi-
al.55,56 Next, we examined β-ketoester nucleophiles. Interest-
ingly, cyclic β-ketoesters afforded exclusively O-alkylation
products; however, acyclic β-ketoesters, such as 10, proved
to be competent C-nucleophiles. Accordingly, known β-
ketoester 10 was treated with sodium hydride and the iodide
derived from 21, smoothly affording alkyne 22 in 85% yield.
At this juncture, we identified two possible avenues for
construction of the spiroketal and the C7, C10, and C11
stereocenters of leonuketal (1). Typically, dihydroxy alkynes
are employed in Au-catalyzed spiroketalizations. However, 22
was a mixture of C10 epimers and reduction of the C11 ketone
would likely have afforded four diastereomers. Instead, we
elected to explore the Au-catalyzed spiroketalization of β-
ketoester 22 without first reducing the C11 ketone. This
transformation of β-ketoesters had not, to the best of our
knowledge, been reported previously.
Figure 1. Background and retrosynthetic analysis; NB: numbering in
1B based on parent labdane skeleton.
Initial investigations yielded the desired spiroketal product
upon treatment of 22 with Au(I)-complexes; however, these
results had poor reproducibility, and this process often resulted
in decomposition of the substrate. We therefore sought an
alternative spiroketal precursor.
TBS deprotection and lactonization of 22 afforded cyclic β-
keto(enol)lactone 8, as an alternative spiroketalization
substrate. To our delight, treatment of 8 with AuCl·DMS
and PPTS reliably delivered spiroketal 7 in 65% yield and with
an excellent 9:1 dr, thereby demonstrating this previously
unexplored class of substrates to be viable Au-catalyzed
spiroketalization precursors.
Figure 2. Discussion of auxiliary ring strategy for synthesis of 18.
Investigation of 8 as a spiroketalization substrate was
prompted by considering the loss of entropy incurred by
formation of the rigid caged spirocycle. Straight-chain β-
ketoester 22 had greater conformational freedom than the
cyclic congener 8. Hence, the loss of entropy upon forming 7
from 8, particularly in preventing rotation of the C10−11
bond, would have been less than for the spiroketalization of
Such substrates lacked the rigidifying auxiliary pyran ring of
13 and, as a result, exhibited more conformational freedom.
Indeed, the diastereoselectivity observed for formation of 11
may have been enhanced by the rigidity imposed by the
B
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a
Scheme 1. Total Synthesis of ( )-Leonuketal (1)
a
Reagents and conditions: (a) Cp2TiCl2 (2.2 equiv), Zn (4.6 equiv), THF, 60 °C, 1 h then aq. KH2PO4, rt, 30 min, 32%; (b) ethylene glycol (15
equiv), TsOH (5 mol %), benzene, reflux, 4 h; (c) DMP (1.2 equiv), pyridine (2.5 equiv), CH2Cl2, rt, 1 h, 77% over 2 steps; (d) L-selectride (2.2
equiv), THF, −78 °C to rt, 1.75 h; (e) 3 M HCl-THF (1:3, v/v), 40 °C, 16 h, 78% over 2 steps; (f) NH2NHTs (1 equiv), PPTS (5 mol %), THF,
rt, 16 h; (g) MeLi (9 equiv), THF-Et2O (1:1, v/v), 0 °C, 3 h, 89% over 2 steps; (h) TIPSOTf (1.2 equiv), DIPEA (3 equiv), 50 min, 91%; (i)
paraformaldehyde (12 equiv), MeLi (9 equiv), Et2O, −78 to 0 °C, 1.5 h, 94%; (j) MsCl (1.1 equiv), Et3N (1.5 equiv), CH2Cl2, 0 °C, 40 min; (k)
NaI (2.2 equiv), acetone, rt, 16 h; (l) 10 (3 equiv), NaH (2.9 equiv), THF, 0 °C to rt, 16 h, 81% (over 3 steps); (m) TsOH (10 mol %), MeOH, rt,
16 h then K2CO3, rt, 4 h, 84%; (n) AuCl·DMS (10 mol %), PPTS (1 mol %), rt, 60 h, 65% combined, dr 9:1; (o) H2 (65 psi), Rh−Al2O3, MeOH,
rt, 60 h, 98%. 1:1.2 23−24; (p) 1 N LiOH-THF (1:3, v/v), rt, 16 h; (q) DMP (4 equiv), CH2Cl2, rt, 30 min; (r) PPTS (10 mol %), EtOH, 45 °C,
24 h, 84% over 3 steps from 23 (39% from 23−24 combined); (s) TBAF (5 equiv), THF, 40 °C, 2 h; (t) DMP (4 equiv), K2CO3 (7 equiv),
CH2Cl2, rt, 30 min; (u) nPrMgBr (1.85 equiv), Et2O, 0 °C, 1 h, (v) DMP (4 equiv), K2CO3 (7 equiv), CH2Cl2, rt, 30 min, 57% over 4 steps; (w)
O2, LiHMDS (34 equiv), THF, −78 °C, 3.3 h then P(OEt)3 0.5 h, 48% combined (60% brsm), dr 1:1; thermal ellipsoids set at the 50% probability
level.
straight-chain substrate 22. This substrate modification proved
instrumental to the reliable formation of the caged spiroketal of
1.
desired product 23 (see the Supporting Information (SI)),
indicating that nonselective hydrogenation would result in the
observed mixture of 23 and 24, as was observed
experimentally.
The next challenge in our total synthesis was the
diastereoselective reduction of the enol ether of 7. We posited
that hydrogenation at the α-face could be achieved if a
haptophilic effect of the posterior spiroketal oxygen (Scheme 1,
green) directed adsorption of 7 at this face of the molecule.57
After some experimentation, rhodium on alumina was revealed
to be a competent catalyst for hydrogenation of 7 at elevated
pressure (65 psi); however, the desired α-face addition product
23 was accompanied by diastereomer 24 as an inseparable
1:1.2 mixture.58,59 Interestingly, 24 bore inverted stereogenic
centers at C10, C11, and the spiroketal carbon C7.
The observed mixture of 23 and 24 appears most likely to
arise from nonselective hydrogenation of 7 from either face of
the alkene, to initially give a mixture of the desired
hydrogenation product 23 and 7-epi-24, respectively. Sub-
sequent thermodynamically driven spiroketal epimerization of
7-epi-24 to 24 would then afford the observed product mixture.
Calculations suggested that C7 epimerization should be
favorable for β-face addition product 7-epi-24 but not for the
The diastereomeric mixture 23 and 24 was then advanced to
the fully elaborated ketal-γ-lactone portion of leonuketal (1).
This was achieved by lactone hydrolysis, oxidation of the
liberated alcohol, and acid-mediated acetalization to afford 25
as a single C12 epimer in over three steps. This sequence
required only one chromatographic separation after acetaliza-
tion, at which point, the desired diastereomer 25 could be
separated from the product derived from 24 (not shown).
Completion of 25 secured the unique tetracyclic core of
leonuketal (1) and all but one chiral center for the total
synthesis. An X-ray structure of 25 allowed us to confirm the
stereochemical configuration matched that of leonuketal (1).
With 25 in hand, the endgame of our total synthesis could
be investigated. Deprotection of 25 proceeded smoothly at
slightly elevated temperature, and the free alcohol was oxidized
with DMP immediately to prevent possible transketalization.
The aldehyde was treated with propylmagnesium bromide
then oxidized directly to afford deoxyleonuketal (26) in 57%
C
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yield over four steps with only two chromatographic
separations. α-Hydroxylation of the newly formed ketone 26
was the final step in completion of the total synthesis and
required some investigation (see Tables S4 and S5, SI).
Deprotonation of 26 with LiHMDS followed by treatment
with (1S)-(+)-(10-camphorsulfonyl)oxaziridine effected the
desired oxidation, but favored the formation of 15-epi-
leonuketal (epi-1) with a 9:1 dr. Surprisingly, the use of
Davis’ oxaziridine under analogous conditions delivered no
detectable amount of 1 or epi-1 at either full or partial
consumption of starting material. Fortunately, bubbling
molecular oxygen through a solution of deprotonated 26
delivered leonuketal (1), alongside 15-epi-leonuketal (epi-1), in
48% yield (60% brsm) and 1:1 dr after reductive workup.
Leonuketal (1) was separated from epi-1 by reverse phase
HPLC, and to our delight, the NMR data were in good
agreement with the isolation report (Tables S6 and S7, SI).11
In summary, we report the first total synthesis of complex
seco-labdane leonuketal (1) over 23 steps from 12.60 Successful
completion of the synthesis was enabled by development of
three key transformations: the Ti(III)-mediated cyclization of
12, the unusual Shapiro-type fragmentation of 11 as part of an
auxiliary ring strategy, and the previously undescribed Au-
catalyzed spirocyclization of a β-keto(enol)lactone (7) . We
anticipate that these extensions to the synthetic toolkit will find
wider application in the preparation of complex structures and
that ongoing investigations into the chemistry and biology of
natural product frameworks exemplified by 1, and more
particularly 18, will prove to be fruitful fields of research.
Centre for Molecular Biodiscovery, Auckland 1010, New
Zealand; orcid.org/0000-0001-7077-8756
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03364
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the University of Auckland for the Doctoral
Scholarship Award (PSG) and Dr. Tania Groutso (UoA) for
assistance with crystallography.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03364.
Experimental procedures and analytical data (1H and
13C NMR, MS, IR) for all compounds (PDF)
Accession Codes
CCDC 2017573−2017575 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
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.
AUTHOR INFORMATION
■
Corresponding Authors
Margaret A. Brimble − School of Chemical Sciences, University
of Auckland, Auckland 1010, New Zealand; Maurice Wilkins
Centre for Molecular Biodiscovery, Auckland 1010, New
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Daniel P. Furkert − School of Chemical Sciences, University of
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