Total synthesis of the Cephalotaxus norditerpenoids (±)-cephanolides A-D

Article abstract of DOI:10.1021/jacs.1c00293

Concise syntheses of the Cephalotaxus norditerpenoids cephanolides A-D (8-14 steps from commercial material) using a common late-stage synthetic intermediate are described. The success of our approach rested on an early decision to apply chemical network analysis to identify the strategic bonds that needed to be forged, as well as the efficient construction of the carbon framework through iterative Csp²-Csp³ cross-coupling, followed by an intramolecular inverse-demand Diels-Alder cycloaddition. Strategic late-stage oxidations facilitated access to all congeners of the benzenoid cephanolides isolated to date.

Full text of DOI:10.1021/jacs.1c00293

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Total Synthesis of the Cephalotaxus Norditerpenoids
( )-Cephanolides A−D
Maximilian Haider,§ Goh Sennari,§ Alina Eggert, and Richmond Sarpong*
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ABSTRACT: Concise syntheses of the Cephalotaxus norditerpenoids cephanolides A−D (8−14 steps from commercial material)
using a common late-stage synthetic intermediate are described. The success of our approach rested on an early decision to apply
chemical network analysis to identify the strategic bonds that needed to be forged, as well as the efficient construction of the carbon
framework through iterative Csp2−Csp3 cross-coupling, followed by an intramolecular inverse-demand Diels−Alder cycloaddition.
Strategic late-stage oxidations facilitated access to all congeners of the benzenoid cephanolides isolated to date.
mong the many considerations in developing a total
synthesis of a structurally complex molecule is max-
biosynthetically related to the Cephalotaxus diterpenoids
harringtonolide (5)7 and fortalpinoid G (6).8 The larger
family of Cephalotaxus diterpenoids9 have shown a broad range
of bioactivity that includes plant growth inhibition as well as
antineoplastic, antiviral, and antitumor properties.10−14 Pre-
liminary bioactivity studies of the cephanolides by Yue et al.15
suggest that the A-ring (see I, Scheme 1C, for lettering and
numbering), along with its oxygenation, may be essential to
their cytotoxic activity against human cancer cell lines. Their
interesting frameworks and bioactivity have spurred many
creative and informative total syntheses of the troponoid
diterpenoid harringtonolide (5) and congeners over the past
20 years.16−19 Owing to their more recent isolation, it is only
over the past three years that syntheses of the benzenoid
cephanolides have been reported. In 2018, Zhao et al. reported
the total syntheses of cephanolides B and C (2 and 3; Scheme
1A) using an innovative Pd-catalyzed carbonylative Heck
cascade.20 In 2020, Gao and co-workers reported an effective
synthesis of cephanolide A (1) that relied on the application of
a Prins-type cyclization (Scheme 1B).21 Recently, they have
also synthesized 2.22
A
imizing the rapid generation of target relevant structural
complexity in the forward sense. Therefore, in the retro-
synthetic analysis of structurally complex natural products,
disconnections that achieve maximum simplification are highly
sought after. Bicyclization transforms are broadly recognized to
be powerful in this regard.1 We have found that chemical
network analysis,2−4 which is rooted in seminal reports from
Corey,5 provides an expedient guideline for identifying the
strategically most important bonds for this purpose. The
benzenoid cephanolide diterpenoids (1−4, Figure 1) pre-
In our chemical network analysis of the cephanolide
framework, we identified two maximally bridged rings (see
rings highlighted in blue in V and VI, Scheme 1C). On this
basis, three bicyclization disconnections were identified,
leading to the hypothetical precursors II, III, and IV. Of
these possibilities, II would lead to the maximum increase in
target-relevant structural complexity given the attendant
generation of four stereocenters in this process. As we
considered the appropriate substrate for a planned intra-
molecular Diels−Alder cycloaddition to forge the framework of
Figure 1. Selected benzenoid and troponoid Cephalotaxus diterpe-
noids.
sented an opportunity to test aspects of this type of approach.
In addition to identifying strategic disconnections that would
ultimately result in the efficient preparation of any of the
benzenoid cephanolide congeners isolated to date, we sought
to identify a route that could be applied to the synthesis of any
of the Cephalotaxus diterpenoids. In this Communication, we
report our initial studies that have led to the realization of our
first goal.
Received: January 9, 2021
Published: February 12, 2021
Cephanolides A−D were isolated in 2017 from Cephalotaxus
sinensis by Yue and co-workers.6 They are structurally and
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pyrone−triflate 16, which would be linked with an appropriate
two carbon fragment (15) via an iterative cross-coupling
sequence.
Scheme 1. (A) Key Transformations in Zhao’s Total
Synthesis of Cephanolides B and C; (B) Key
Transformations in Gao’s Asymmetric Total Synthesis of
Cephanolides A and B; (C) Chemical Network Analysis of
the Cephanolide Framework; (D) [4 + 2] Cycloaddition
Strategy Identified through Network Analysis
Our syntheses commenced with the triflation of commer-
cially available 7-hydroxy-4-methylindanone (17, Scheme
2A).30 Pyrone triflate 16 was prepared from mucic acid
following a known sequence reported by the group of
Maulide.31 Iterative sp2−sp3 Suzuki cross-couplings of BF3K-
ethylene-9BBN (15), generated in situ from hydroboration of
vinylBF3K, with 14 and then 16 was accomplished following
the precedent established by Molander and co-workers.32−34
This sequence proceeded on a multigram scale with only one
chromatographic purification to provide indanone derivative
11 in 80% yield (over two steps). In preparation for the crucial
intramolecular Diels−Alder cycloaddition, we sought to
prepare various enol ethers of indanone 11. We were pleased
to observe that the cycloaddition proceeded smoothly under
conditions to form the silyl enol ether to provide the somewhat
unstable endo cycloadduct (13). Analysis of the X-ray
crystallographic data of a single crystal of 13 unambiguously
confirmed its structure. Optimization of this cascade silyl enol
formation/[4 + 2] cycloaddition revealed that two equivalents
of TMSOTf were required. Presumably, the first equivalent
leads to the formation of the enol ether, while the second
equivalent likely serves as a Lewis acid for the cyclo-
addition.35−37 We next sought to functionalize the bridging
olefin group of 13. Various attempted hydroborations as well
as epoxidation of the olefin group failed, in line with
observations made by Mander et al. on a similar bridged
[2.2.2] bicycle that also bears a lactone.25 The recalcitrance of
the olefin group to react under these conditions was attributed
by Mander to its electron deficiency by virtue of the attached
electron-withdrawing lactone. Therefore, instead of electro-
philic reagents for olefin functionalization, we chose to focus
on hydrogen atom transfer (HAT) processes.38 We were
pleased to find that a variant of the Mukaiyama hydration
protocol, developed by Inoue et al. for their ryanodol
synthesis,39,40 proved particularly effective for our purposes.
Thus, ketone 20 (confirmed by X-ray crystallographic analysis)
was obtained from 13 through a one-pot protocol in moderate
yield. The regioselectivity of the initial hydrocobaltation likely
results from a directing effect by the proximal oxygen lone pair
of the lactone. For optimal results, the Inoue protocol had to
be modified to avoid the use of excess DBU, which was needed
for converting a nonaflate peroxide, generated from TES
peroxide 19, to 20. Excess DBU caused enolization of the
resulting ketone group in 20, followed by decarboxylation from
the strained lactone at temperatures higher than −78 °C. This
inherent lability of the bridged bicyclo[2.2.2]lactone also
manifested itself in the subsequent olefination of ketone 20 to
exo-methylene 21. Initial Wittig olefination attempts failed, as
phosphorus ylides proved to be too basic, even at cryogenic
temperatures and resulted in opening of the lactone. Cognizant
of the base lability of 20, we focused our efforts on olefination
reagents that are known to be less basic. From our
investigations of the Tebbe,41 Petasis,42 Johnson-Peterson,43
Kauffmann,44 Nystedt,45,46 and Lombardo47 olefinations, only
the latter two delivered trace amounts of 21. While we were
unable to improve the yield and/or scalability using the initially
published Lombardo protocol, the observed reactivity of the
combination of CH2Br2/Zn/TiCl4 led us to investigate similar
1−4, we settled on indanone−pyrone 11 (Scheme 1D), which,
via enol 12 (rendered in a conformation approaching the
transition state), should facilitate the anticipated inverse-
demand intramolecular [4 + 2] cycloaddition.23−29 The
desired endo cycloadduct 13 would therefore bear oxygenation
at C10, lending itself directly to the syntheses of 3 and 4 but
necessitating a deoxygenation to access 1 and 2. However, 13
appeared ideally suited for the myriad late-stage functionaliza-
tions of the arene moiety as well as the C7 and C20 benzylic
positions that would be required to access all the known
cephanolide congeners. Finally, we envisioned indanone−
pyrone adduct 11 arising from indanone−triflate 14 and
reagent combinations.48−54 Gratifyingly, a slight modification
55
́
of an olefination protocol published by Barnych and Vatele,
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Scheme 2. Total Syntheses of Cephanolides A, B, C, and D
employing a combination of Ti(Oi-Pr)2Cl2 and the Nystedt
reagent, gave exo-methylene 21 in 53% yield. The reaction
could be routinely performed on a 500 mg scale. The synthesis
of 21 set the stage for late-stage manipulations to access
cephanolides A−D.
We were pleased to find that heterogeneous hydrogenation
of 21 with Pd/C in MeOH delivered the desired stereo-
chemistry at C4 (d.r. = >20:1) of 22 in almost quantitative
yield. While the reason for this selectivity is not immediately
obvious, it may be that the nucleophilicity of the two π-faces of
the exo-methylene differ by virtue of stereoelectronic
interactions on one face with the π*-orbital of the lactone
carbonyl group as proposed by Woodward.56−58 Thus,
hydrogenation occurs from the less electron-depleted face.
Deprotection of the C10 tertiary hydroxy group of 22 (TBAF
in THF) and subsequent ionic deoxygenation (InCl3/
Ph2SiHCl)59,60 furnished 23 in 97% yield. Phthaloyl peroxide
in HFIP, following the precedent of Siegel et al.,61 effected
direct oxygenation of the arene moiety to give the desired
phenol in 42% yield along with 32% of the constitutional
phenol isomer. This direct, albeit modestly selective, oxidation
yielded cephanolide B (2) in 10 steps from 7-hydroxy-4-
methyl-1-indanone (17).
To access cephanolide C from 22, all that was required was a
selective oxidation of the C7 benzylic position and
deprotection of the tertiary alcohol. Selective C7 benzylic
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oxidation had already been demonstrated by Zhao and co-
workers in their synthesis of cephanolides B and C.20 Using
these conditions, along with a strong acid work-up, we realized
the C7 oxygenation along with TMS cleavage in one pot to
access cephanolide C (3) in 54% yield from 22 (eight steps
from 17).
with the C15 hydroxylated constitutional isomer), in 14 steps
from 17.
In summary, on the basis of a retrosynthesis guided by
chemical network analysis, we have developed highly concise
syntheses of cephanolide A (1, 14 steps), cephanolide B (2, 10
steps), cephanolide C (3, 8 steps), and cephanolide D (4, 14
steps) from a commercially available indanone (17). A key
design element of our synthesis plan was to identify a common,
versatile intermediate that could be applied to preparation of
all the cephanolide congeners. Our approach features rapid
construction of the core framework of the cephanolides by
employing an iterative Csp2−Csp3 cross-coupling, followed by
an enol ether/intramolecular inverse-demand Diels−Alder
reaction. We also showcased late-stage oxygenation tactics as
a powerful tool for achieving efficient peripheral structural
diversification. Our synthesis plan sets the stage for the
preparation of other structurally complex Cephalotaxus
norditerpenoids that involve scaffold modifications. These
efforts, as well as the development of an enantioselective
variant of the intramolecular Diels−Alder reaction applied
here, are the subject of ongoing studies in our laboratory.
To access cephanolide D, we effected the same benzylic
oxidation of 22 using PCC but left the tertiary hydroxy group
protected by using slightly modified conditions. We explored,
without success, many ketone62 and other carbonyl-based
auxiliaries in attempts to achieve directed C−C bond-forming
ortho C−H functionalization63−65 of 3 and its derivatives. Our
failure to install the methyl ester directly necessitated the
following effective, albeit indirect, approach. The ketone
installed at C7 of 22 was converted to the acetyl oxime by
condensation with hydroxylamine and subsequent acetylation
in the same pot to afford 24. Oxime-directed ortho C−H
acetoxylation following the precedent of Sanford et al.66
successfully functionalized the arene at C15. Global cleavage of
the acetyl groups, followed by oxidative removal of the
oxime,67 gave hydroxyketone 25 in 33% yield over the four
steps. Of note, while Sanford successfully employed free
oximes in ortho acetoxylations through in situ acetylation of
the oxime, in our case, the free oxime was not easily acetylated
under the acetoxylation conditions (AcOH/Ac2O, heating),
resulting in its oxidative cleavage to give the precursor ketone.
Finally, phenol 25 was treated with Tf2O in pyridine to give
the corresponding triflate (84% yield), which was then
subjected to Pd-catalyzed methoxy carbonylation and a
subsequent one-pot deprotection of the tertiary alcohol to
afford cephanolide D (4) in 93% yield (14 steps from 17).
Lastly, we addressed the synthesis of cephanolide A (1) from
common intermediate 21 (Scheme 2B). While the syntheses of
cephanolides B−D arose directly from reduction of the exo-
methylene group of 21, the synthesis of 1 required the
installation of a hydroxy group at C3. For this purpose, we
employed an allylic oxidation. Analyses of the crystal structures
of 13 or 20 indicated that the oxygenation was likely to occur
from the undesired convex face. Therefore, the allylic alcohol
resulting from SeO2 oxidation of 21 was oxidized to give an
enone (26) in one pot by using DMP in 76% yield.
Hydrogenation of 26 (Pd/C in MeOH), followed by
epimerization of the methyl-bearing stereocenter of 27, gave
the desired ketone (28) in 52% yield over two steps. Reduction
of the ketone group with NaBH4 delivered alcohol 29, which
was subjected to Suarez oxidation conditions68,69 employing I2
and PIDA to forge the desired THF ring without an event. The
free tertiary alcohol was obtained after TMS cleavage in the
same pot (98% yield over two steps), underlining the power of
the Suarez variant of the 1,5-HAT process for late-stage
oxygenation. Surprisingly, the resulting tertiary alcohol did not
undergo ionic deoxygenation under the same conditions59,60
that had worked in the cephanolide B synthesis. As a
consequence, we had to concede to a two-step procedure of
xanthate preparation followed by classical Barton−McCombie
deoxygenation to give 31 in 82% yield over two steps.
Oxygenation of the arene moiety of 31 using phthaloyl
peroxide61 as employed in the final step en route to 2 did not
afford the desired phenol in this case. Ultimately, we found
that 31 was oxygenated using the cyclopropane malonyl
peroxide,70 which was identified after an extensive survey of
reagents, to provide cephanolide A (1) in 39% yield (6:1 ratio
ASSOCIATED CONTENT
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* Supporting Information
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https://pubs.acs.org/doi/10.1021/jacs.1c00293.
Experimental details and spectroscopic data (PDF)
Accession Codes
CCDC 2058197−2058198 contain the supplementary crys-
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AUTHOR INFORMATION
■
Corresponding Author
Richmond Sarpong − Department of Chemistry, University of
California, Berkeley, Berkeley, California 94720, United
States; orcid.org/0000-0002-0028-6323;
Email: rsarpong@berkeley.edu
Authors
Maximilian Haider − Department of Chemistry, University of
California, Berkeley, Berkeley, California 94720, United
States
Goh Sennari − Department of Chemistry, University of
California, Berkeley, Berkeley, California 94720, United
States
Alina Eggert − Department of Chemistry, University of
California, Berkeley, Berkeley, California 94720, United
States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00293
Author Contributions
§M.H. and G.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
R.S. thanks the NSF under the CCI Center for Selective C−H
functionalization (CHE-1700982) and the National Science
Foundation (CHE-18566228) for support. G.S. thanks the
Uehara Memorial Foundation for a postdoctoral fellowship.
A.E. thanks Leibniz PROMOS for support of a visiting student
stay at UC Berkeley. We thank Dr. Hasan Celik and UC
Berkeley’s NMR facility in the College of Chemistry (CoC-
NMR) for spectroscopic assistance. Instruments in CoC-NMR
are supported in part by NIH S10OD024998. We are grateful
to Dr. Nicholas Settineri (UC Berkeley) for X-ray crystallo-
graphic studies of 13 and 20 and Dr. Rita Nichiporuk (UC
Berkeley) for mass spectrometric analysis.
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