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org/JACS Communication
Enantioselective Total Synthesis of (+)-Peniciketals A and B: Two
Architecturally Complex Spiroketals
Yifan Deng, Chia-Ping H. Yang, and Amos B. Smith III*
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ABSTRACT: The enantioselective total syntheses of (+)-peniciketals A and B, two members of a family of architecturally complex
spiroketals, have been achieved. Key synthetic transformations comprise Type I Anion Relay Chemistry (ARC) to construct the
benzannulated [6,6]-spiroketal skeleton, a Negishi cross-coupling/olefin cross-metathesis reaction sequence to generate the trans-
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enone structure, and a late-stage large fragment union exploiting our recently developed photoisomerization/cyclization tactic.
T he peniciketals A−C (1−3; Scheme 1), architecturally
complex spiroketals, isolated in 2014 from the fungus
Scheme 1. (+)-Peniciketal A−C
Penicillium raistrickii found in saline soil samples isolated from
Bohai Bay (China), display cytotoxicity against HL-60 cells
with IC50 values of 3.2, 6.7, and 4.5 μM, respectively.1
Peniciketal A (1), in particular, proved to be cytotoxic, with
time-dependent inhibition/proliferation of the human non-
small lung cancer cell line A549 (IC50 = 22.33 μM in 72 h) as
well as inhibition of both migration and invasion of A549 cells
by reducing the levels of the MMP-2 and MMP-9 protein.2
More recently, peniciketal A (1) was also revealed to reduce
cell proliferation in three leukemia cell lines3,4 and had high
selectivity for cancer cells with lower toxicity toward normal
cells (L02, MRC5, and MEFs).2,3 This high level of antitumor
activity recently led to more mechanistic studies including a
global proteomic profile of peniciketal A (1),4 which suggests
that this natural product may possess additional bioactivities
and as such constitutes a promising drug lead candidate.
The structures of the peniciketals are unprecedented in the
literature, comprising one phenyl ring fused not only to a
[6,6]- or [5,6]-spiroketal but also to a 2,8-dioxabicyclo-
[3.3.1]nonane moiety. Such benzannulated spiroketals, espe-
cially those possessing a [6,6]-spiro-ring, are relatively rare in
nature, and as such have led to significant synthetic efforts in
past two decades.5 From our perspective, we envisioned our
Type I Anion Relay Chemistry (ARC), a multicomponent
union protocol developed for the elaboration of structurally
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sı Supporting Information
complex scaffolds,6 could be an effective tactic to access rapidly
such aryl spiroketals. Equally significant, the unique benzo-
fused 2,8-dioxabicyclo[3.3.1]nonane framework is also a
challenging framework for current synthetic methods. For
example, transition-metal-catalyzed asymmetric Michael addi-
tion,7 followed by acid-mediated ketalization to construct such
structures, is particularly difficult in the presence of free
hydroxy, carbonyl, spiroketal, and/or phenol groups. Attracted
by the challenging architecture and extensive biological
activities, we initiated a synthetic program toward peniciketals
A (1) and B (2), exploiting Type I ARC and our newly
developed photochemical protocol (vide infra) to construct the
complex benzo-fused [3.3.1]nonane core, the latter in a single
step.
Having a long-standing interest in developing novel
photochemical protocols for total synthesis, see the panicu-
lides,8 hibiscone C,9 echinosporin,10 and recently the
danshenspiroketallactones,11 etc., we disclosed in 2015 a
tandem photoisomerization/cyclization tactic to construct
cyclic and spirocyclic ketals (Scheme 2a).12 Pleasingly, this
mild photochemical protocol proceeds with high diastereose-
lectivity (dr >20:1) and therefore holds great potential for the
construction of complex polycyclic structures when extended
to an intermolecular version. For example (Scheme 2b),
irradiation (355 nm) of trans-enone A in mild acid was
envisioned to give rise to a mixture of olefin isomers with the
cis-isomer B and then undergo cyclization to deliver diene C.
Under the acidic conditions, C could then protonate to
generate oxonium D. This electrophilic intermediate is
structurally rigid and could then lead to a stereoselective [3
+ 3] cyclization with electron-rich aromatic nucleophiles to
Received: November 3, 2020
Published: January 26, 2021
https://dx.doi.org/10.1021/jacs.0c11424
1740 J. Am. Chem. Soc. 2021, 143, 1740−1744
Journal of the American Chemical Society
Scheme 2. Tandem Photoisomerization/Cyclization
access the unique benzo-fused 2,8-dioxabicyclo[3.3.1] nonane
structure E in a one-pot fashion.
With this overview, the [3.3.1] nonane core of peniciketal A
would be disconnected to yield the northern hemisphere (4)
and benzannulated [6,6]-spiroketal (5) as the southern
hemisphere (Scheme 3), exploiting the above proposed late-
Scheme 3. Retrosynthetic Analysis
stage photoisomerization/cyclization union tactic. The north-
ern hemisphere (4), a highly functionalized trans-enone, was
anticipated to be constructed via a Negishi cross-coupling/
olefin cross-metathesis reaction sequence, involving ester 6,
acryloyl chloride 7, and commercially available homoallylic
alcohol (+)-8. The southern hemisphere (5) in turn would
derive from linear precursor 9, possessing the 1,3,5-triol
functionality, well-suited for our Type I ARC, employing
linchpin 11 and two different electrophiles 10 and (+)-12.13
We first conducted a model reaction (Table 1) to validate
the intermolecular photochemical protocol with enone (+)-13
(see Supporting Information) and commercial resorcinol 14.
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pubs.acs.org/JACS Communication
Table 1. Model Studies of the Photochemical Protocol
entry Bronsted acid concentration (M) yielda(%) of 15
1 PTSA (20 mol %) 0.1 45
2 PTSA (20 mol %) 0.2 71
3 CSA (20 mol %) 0.2 80
4 PPTS (50 mol %) 0.2 49
5b CSA (20 mol %) 0.2 NR
a
Reaction conditions: (+)-13 (0.2 mmol), 14 (0.2 mmol), Bronsted
acid (cat.), in THF, rt, UV-A light (λ = 355 nm), 24 h. The isolated
yields of products (+)-15 were obtained by flash chromatography.
The dr was measured by 1H NMR. bNo light. NR = no reaction, and
both starting materials remained.
Pleasingly, the desired bicyclo[3.3.1]nonane (+)-15 was
obtained in 45% yield with high diastereoselectivity (entry 1,
dr > 20:1). The key intermediate diene (+)-16 was isolated,
which was resubjected into acidic conditions with 14 to yield
(+)-15 without UV-A light. Further optimization indicated
that with camphor sulfonic acid (CSA) as the Bronsted acid in
conjunction with more concentrated solutions, the yield
increased to 80% (entry 3). A control experiment demon-
strated the essential role of UV-A light (entry 5). Neither
isomerization nor cyclization occurred when the reaction was
conducted in the dark.
With the success of the model study, we initiated the
synthesis of peniciketal A (1) with construction of the
southern hemisphere (5), employing Type I ARC as outlined
in Scheme 4. The known compound 18 was prepared from 17
Scheme 4. Synthesis of the Southern Hemisphere
in 47% yield by a 5-step sequence.14 Benzyl bromide 10 was
then prepared from 18 in 3 steps. The ARC process was then
initiated by deprotonation of the dithiane linchpin 11 with n-
BuLi, followed by the addition of epoxide (+)-12. The
resulting alkoxide 19 then underwent a [1,4]-Brook rearrange-
ment,15 triggered by the addition of HMPA to relay the
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negative charge via silyl group migration from the dithiane Scheme 6. Total Synthesis of (+)-Peniciketal A
carbon in 19 to oxygen in 20. Carbanion 20 was then captured
with benzyl bromide 10 to deliver the desired three-
component adduct 21, which was subjected to dithiane
removal with simultaneous hydrolysis of the TMS ether to
provide linear precursor (+)-9 in a total yield of 64% for the 2
steps on a 2 g scale. At this stage, a variety of conditions was
explored for global removal of TBS groups, including TBAF,
TBAF/HOAc buffer, HF/pyridine, PTSA/MeOH, and other
acidic conditions, but only poor results were obtained.
Pleasingly, however, the gold-catalyzed deprotection protocol
of Zhang et al.16 enabled the selective deprotection of two
aliphatic TBS ethers with simultaneous cyclization to deliver
spiroketal (−)-22 as a single diastereomer! We envision the
high diastereoselectivity to be due to the anomeric effect17 and
presumably a chelation effect of the gold catalyst. Final
removal of remaining phenolic TBS group with TBAF
completed the synthesis of the southern hemisphere (−)-5.
Turning to construct the northern hemisphere, we began
with the naturally abundant/commercially available atraric acid
23, which was first protected with two TBS groups to deliver 6
in 90% yield. Deprotonation of 6 with freshly prepared LiTMP
formed the ortho-ester benzylic anion 24. Pleasingly, anion 24,
with the OTBS group adjacent to the ester that does not
undergo self-condensation,18 was sufficiently stable for further
transmetalation with ZnCl2 and in turn undergoes the desired
Negishi coupling19 with acryloyl chloride 7 to furnish enone 25
in 80% yield. Olefin cross-metathesis between 25 and
homoallylic alcohol (+)-8 in the presence of Hoveyda−Grubbs
II catalyst then produced the northern hemisphere (+)-4 in
84% yield with the enone in the E configuration. It is
particularly noteworthy that the highly functionalized northern
hemisphere (+)-4, bearing an enone, an ester, and a free
hydroxy group, could be constructed in only three steps on
gram scale (Scheme 5).

Scheme 5. Synthesis of the Northern Hemisphere

single step proved unsuccessful. Alternatively, TBS protection

Having arrived at the requisite northern and southern
hemisphere (+)-4 and (−)-5, we next explored the key large-
fragment union employing our photoisomerization/cyclization
tactic (Scheme 6). Pleasingly under UV-A light, the enone
(+)-4 underwent photoisomerization to form the key cyclic
of (−)-27 followed by DIBAL-H reduction furnished alcohol
(−)-29, which under oxidation with Dess−Martin periodinane
(DMP) and silyl group removal with TBAF completed the
total synthesis of (+)-peniciketal A (1). It is also noteworthy
that in the endgame of this synthesis, (−)-27 and (−)-29, once
fully deprotected, could serve as the ester and alcohol
analogues of peniciketal A, which are potentially important
for possible structure−activity relationship studies to improve
the bioactivities.
The NMR spectra of the synthetic (+)-1 are identical to
those of the natural sample. The absolute configuration of
(+)-1 was confirmed by a single-crystal X-ray anomalous
dispersion, which is also identical to the natural product.1 The
optical rotation obtained from crystallized synthetic sample is
[α]20
D = +1.8 (c 1.0, acetone), compared with natural [α]D =
20

oxonium diene intermediate 26 in situ. The hindrance of the
methyl group in 26 then led to a stereoselective [3 + 3]-
cyclization with the bulky nucleophile (−)-5 to furnish the
desired [3.3.1] nonane adduct (−)-27 in 72% isolated yield
(88% based on recovered 5) with a 13:1 dr. The endgame to
complete the total synthesis of peniciketal A then only required
reduction of the ester to aldehyde. Unfortunately, various
attempts to reduce (−)-27 to the corresponding aldehyde in a
1742
+23.7 (c 0.53, acetone). See Supporting Information for
details.
With the success of (+)-peniciketal A, we were encouraged
to continue our synthetic drive to access (+)-peniciketal B (2),
which structurally only differs at the C(3)−OH site of
(+)-peniciketal A. The synthesis began with a Barton−
McCombie deoxygenation20 of (−)-22 (Scheme 7), which
furnished the deoxygenated benzannulated [6,6]-spiroketal
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Scheme 7. Total Synthesis of (+)-Peniciketal B
(−)-30 in 80% yield. Treatment of (−)-30 with TBAF
generated the southern hemisphere (−)-31, required for
(+)-peniciketal B (2). Toward the latter end, the photo-
isomerization/cyclization tactic again pleasingly achieved the
large fragment union of (+)-4 and (−)-31 to furnish the
desired adduct (−)-32 in 73% yield with dr = 12:1. Further
elaboration of (−)-32 with the same reduction/oxidation
sequence as that for (+)-peniciketal A (1) then completed the
total synthesis of (+)-peniciketal B (2), the spectral properties
of which proved to be identical in all respects to those reported
for the natural product. The overall yield for the 8-step
sequence from (−)-22 was 24%.
We further evaluated the cytotoxicity of synthetic (+)-pen-
iciketals A and B against human lung cancer cell lines.
(+)-Peniciketal A (1) showed cytotoxicity against A549 cells
with IC50 values of 16.4 μM, close to the literature report.2 It
also displayed activity against H1975 (IC50 = 14.3 μM).
Pleasingly, we found (+)-peniciketal B (2) is more potent
against both A549 and H1975 cell lines with IC50 values of 6.8
and 7.3 μM, respectively. Synthetic peniciketals A (1) and B
(2) showed less toxicity to human normal lung fibroblast
IMR90 cells with IC50 > 50 μM and IC50 = 38 μM,
respectively.
In summary, the first total synthesis of (+)-peniciketal A (1)
and (+)-peniciketal B (2) was achieved. The total synthesis of
(+)-peniciketal A (1) was achieved with the longest linear
sequence of 17 steps from 17. The central features of this
synthetic venture entailed the further development and
application of a novel photoisomerization/cyclization union
protocol to construct the complex benzo-fused 2,8-
dioxabicyclo[3.3.1]nonane skeleton in conjunction with a
three-component Type I ARC tactic to construct the rare
benzannulated [6,6]-spiroketal. Studies toward the synthesis of
other members of the peniciketal family as well as the
development of analogues for biological evaluations continue
in our laboratory.
■
ASSOCIATED CONTENT
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11424.
1743
pubs.acs.org/JACS Communication
Experimental procedures as well as spectroscopic and
analytical data for all new compounds (PDF)
Accession Codes
CCDC 2041354 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■ AUTHOR INFORMATION
Corresponding Author
Amos B. Smith III − Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United
States; orcid.org/0000-0002-1712-8567;
Email: smithab@sas.upenn.edu
Authors
Yifan Deng − Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United
States
Chia-Ping H. Yang − Department of Molecular Pharmacology,
Albert Einstein College of Medicine, Bronx, New York 10461,
United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11424
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
Financial support was provided by the NIH through Grant
CA-19033 and the Bader fellowship. We thank Dr. C. Ross, III
for HRMS analysis. We thank Dr. Patrick J. Carroll and
Michael Gau for X-ray crystallographic. We thank Dr. David C.
Schultz at the University of Pennsylvania High-Throughput
Screening Core for supporting the in vitro cell viability studies
on IMR90 cells.
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