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Asymmetric Total Synthesis of Pedrolide
Wen Zhang,# Peng-Cheng Yu,# Chen-Yun Feng, and Chuang-Chuang Li*
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ABSTRACT: The asymmetric total synthesis of pedrolide (>200 mg) with an unprecedented [5−5−5−6−6−3] hexacyclic core
(pedrolane) was achieved. Its unique bicyclo[2.2.1]heptane ring system was efficiently constructed via an enantioselective ene
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reaction of cyclopentadiene followed by a Wittig reaction, isomerization, and a diastereoselective intramolecular Diels−Alder
reaction cascade. The highly oxygenated carane [6−3] ring system was synthesized via a ring-closing metathesis reaction followed by
an unusual free carbene cyclopropanation. Furthermore, the 12 contiguous stereocenters of pedrolide were installed
diastereoselectively.
Euphorbia diterpenoids have attracted significant attention
from the related science communities owing to their diverse
complex structures and interesting bioactivities.1 Euphorbia
diterpenoids encompass tiglianes, daphnanes, ingenanes,
jatrophanes, and lathyranes, which show a variety of important
biological activities, such as anti-HIV, anti-inflammatory,
cytotoxic, proinflammatory, and antitumor activities.1 Drug
discovery based on these natural products has led to Picato
(ingenol mebutate), a medicine to treat actinic keratoses,2a and
a candidate drug resiniferatoxin (under phase III clinical trials)
to treat overactive bladder and chronic pain.2b Pedrolide (1,
Figure 1) was isolated from Euphorbia pedroi by Ferreira and
Figure 1. Structural features of pedrolide (1) and its total syntheses.
co-workers in 2021.3 With 5.0 mg available, pedrolide was
found to reverse multidrug resistance mediated by P-
glycoprotein as well as show a strong synergism with
doxorubicin, increasing its cytotoxicity in resistant L5178Y-
MDR cells more than 6-fold. This renders pedrolide a
meaningful synthetic target. Structurally, pedrolide has an
unprecedented carbon skeleton (pedrolane), a [5−5−5−6−6−
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3] hexacyclic core including a unique bridged bicyclo[2.2.1]-
heptane ring system (highlighted in red in Figure 1).
Additionally, the highly oxygenated pedrolide contains 12
contiguous stereocenters, including one all-carbon quaternary
stereocenter at C6 and two oxygenated quaternary stereo-
centers at C9 and C13. Thus, the total synthesis of 1 poses a
daunting challenge.
Recently, Carreira and co-workers achieved a remarkable
first total synthesis of pedrolide in 20 steps (see SI for details).4
Nevertheless, a new approach to access larger quantities of
pedrolide and its analogs is still desirable. As part of our
ongoing efforts on the synthesis of biologically active natural
products, including Euphorbia diterpenoids,5 we herein
describe the asymmetric total synthesis of pedrolide (>200
mg).
Retrosynthetically (Scheme 1), pedrolide (1) could be
generated from 2 through several functional group inter-
conversions (FGIs), mainly including a diastereoselective
cyclopropanation. In turn, compound 2 could be prepared
from 3 via ring-closing metathesis (RCM) reaction, regiose-
lective epoxide-opening reaction, and lactonization. Com-
pound 3 could be produced from 4 via α-allylation and
crotylation of the ketone group. Ketone 4 could be synthesized
from 5 via additional FGIs, mainly including diastereoselective
epoxidation and oxidative cleavage of the p-methoxyphenyl
(PMP) group. The bicyclo[2.2.1]heptane ring system in 5 was
anticipated to be produced through an intramolecular Diels−
Alder (IMDA) reaction from 6.6 Compound 6 could be
prepared from 7 via a Wittig reaction. Finally, compound 7
would be obtained by an enantioselective ene reaction of
cyclopentadiene (8) and trans-p-methoxycinnamaldehyde (9),
although 8 and 9 would undergo a competitive intermolecular
Received: December 14, 2023
Revised: January 23, 2024
Accepted: January 26, 2024
https://doi.org/10.1021/jacs.3c14150
A J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Journal of the American Chemical Society
Scheme 1. Retrosynthetic Analysis of Pedrolide (1)
DA reaction.7 It is worth mentioning that efficiently
constructing the desired 12 contiguous stereocenters in 1
constitutes a significant synthetic issue.
Our synthesis commenced with the synthesis of bicy-
clo[2.2.1] skeleton 5 (Scheme 2). We have adapted and
optimized Hayashi’s enantioselective ene reaction of cyclo-
pentadiene7 to realize a scalable and convenient procedure for
our total synthesis. Pleasingly, the enantioselective ene reaction
of 8 and 9 can be catalyzed by TMS-protected diphenyl
prolinol (10, 10 mol %) in the presence of 11 (20 mol %),
giving a mixture of 7 (1-substituted cyclopentadiene) and its
regioisomer 7a (2-substituted cyclopentadiene) in 75% yield.
The Wittig reaction of 7 and 7a with 12 afforded a mixture of
6 and 6a in 90% yield. As previously reported,6 the IMDA
reaction of 6 and 6a would occur from the most reactive
unseparated regioisomer 6b (5-substituted cyclopentadiene),
which was isomerized from the mixture of 6 and 6a under
heating conditions. To our delight, the anticipated IMDA
reaction of 6 and 6a at 120 °C produced 5 as a single
diastereomer in 72% yield (93% ee). This result showed that it
was not required to separate the regioisomers 6 and 6a.
Furthermore, the above serial reactions from 8 and 9 were
achieved in a one-pot cascade process to give tricycle 5 in 54%
yield (50 g scale). Pleasingly, treatment of 5 with LDA and
MeI provided 13 as a single diastereomer in 82% yield. The
absolute structures of 5 and 13 were established by X-ray
crystallography (see SI for details), respectively. It is interesting
to note that the direct IMDA reaction of 6’s analogue (α-
methyl α,β-unsaturated ester) did not occur to give 13 (see SI
for details). Compound 13 underwent stereoselective epox-
idation of the double bond with m-CPBA, followed by
oxidative cleavage of the PMP moiety with RuCl3 and NaIO4,8a
giving 14 in 68% yield (100 g scale). The resultant carboxylic
acid 14 (30 g scale) was transformed into ketone 4 through a
2-step sequence including a carboxy-inversion reaction8b−f and
Ley oxidation.8g
With 4 in hand, the next challenge was to install the two allyl
moieties diastereoselectively for the RCM reaction (Scheme
2). Initially, treatment of 4 with KHMDS and allyl iodide in
B https://doi.org/10.1021/jacs.3c14150
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Scheme 2. Asymmetric Synthesis of 2
cyclopentyl methyl ether (CPME) at −50 °C provided the
product with undesired C8 stereochemistry (C8-α-H) (see SI
for details). Pleasingly, when treating the resulting product
with KHMDS (1.2 equiv) at −50 °C in one pot, compound 15
with the desired C8 stereochemistry (C8-β-H) was obtained in
71% yield (10 g scale) by the kinetic protonation of the initial
allylation product as a single diastereomer. Crotylation of the
ketone group in 15 with crotyl Grignard chloride (16)
provided a mixture of 3 (11R) and 3′ (11S) at a ratio of 1:2 in
70% yield. Unfortunately, the desired product 3 was the minor
isomer. After extensive investigations (see SI for details), the
diastereoselective crotylation of 15 was eventually achieved
with E-potassium crotyltrifluoroborate (17a) in the presence of
BF3·OEt2 to give 3 as a single diastereomer in 85% yield (8 g
scale).9 Notably, the product 3′ could also be obtained as a
single diastereomer in 70% yield by using Z-potassium
crotyltrifluoroborate (17b) under similar conditions, demon-
strating the robust nature of the crotylation reaction.
The RCM reaction of 3 proceeded smoothly with
Hoveyda−Grubbs II catalyst (HG II, 5 mol %) in DCM to
give 18 in 81% yield (10 g scale). Pleasingly, the sequential
lactonization and regioselective epoxide-opening reaction of 18
were achieved by using LiCuMe2, and the resultant alkoxide
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Journal of the American Chemical Society
reacted with BnBr in one pot to provide 2 in 75% yield (10 g
scale). The absolute structure of 2 was confirmed by X-ray
crystallography of its analogue (see SI for details). Moreover,
this above synthetic route provided an appropriately large
quantity of 2 (>80 g), confirming the reliability of this
approach.
Next, we focused on the final stage of our total synthesis by
the construction of the highly functionalized cyclopropane
ring. Interestingly, Wender10a,11 and Baran12 have reported
elegant approaches for making similar cyclopropane rings of
carane fragments. However, after testing several substrates
(e.g., I, III, or V) and using different approaches respectively
(Figure 2, see SI for more details), none of the desired
Figure 2. Selected unsuccessful attempts to construct the desired
cyclopropane ring.
products (e.g., II or IV) were obtained. It was found that the
C9-lactone moiety, which was not present in previous
approaches, has unfavorable effects (such as tending to
eliminate). Accordingly, the desired cyclopropanation proved
more challenging than expected. Thereafter, we envisaged that
compound 20 would be a stable and effective precursor for the
desired cyclopropanation13 (Scheme 3). Indeed, the double
bond in 2 underwent diastereoselective dihydroxylation using
K2OsO4·2H2O and NMO, followed by selective oxidation of
the less hindered C13-hydroxyl group by TEMPO in one pot
to give 19 in 85% yield (4 g scale). Treatment of 19 with
KHMDS, DIPEA, and HMPA in THF, followed by MOMBr,
provided 20 in 60% yield (2 g scale). With 20 in hand, we
initially explored direct cyclopropanation with dimethylcarbe-
ne.13a Regrettably, no reaction occurred at −78 °C, and
prolonging the reaction time or raising reaction temperature
resulted in gradual decomposition of the substrate. Alter-
natively, MOM enol ether 20 underwent a free carbene
cyclopropanation using CHBr3 and NaOt-Bu in petroleum
ether (PE), followed by gem-dimethylation in the presence of
LiCuMe2 and MeI,13b giving 21 in 40% overall yield. It is
worth mentioning that the cyclopropanation reaction using
enol silyl ether or enol ester substrates was found to be
C https://doi.org/10.1021/jacs.3c14150
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Scheme 3. Total Synthesis of (+)-Pedrolide
problematic during our preliminary investigations (see SI for
details). Moreover, this free carbene cyclopropanation allows
access to over 1.5 g of 21 with the carene [6−3] ring system
bearing desired C12 and C13 hydroxyl moieties.13e,14
As shown in Scheme 3, the two MOM groups in 21 were
removed by 3 N HCl to provide diol 22 in 87% yield. To
complete the total synthesis of 1, selective esterifications of the
C12 and C13 hydroxyl groups in 22 were explored.
Interestingly, during Wender’s elegant previous synthesis, the
C13 hydroxyl group on the similar carane fragment proved to
be a more reactive site for the esterification than the C12
hydroxyl group.4,15 However, we found that the C12 hydroxyl
group in 22 was more reactive than the C13 hydroxyl group,
and chemoselective sequential esterifications of the C12 and
C13 hydroxyl groups proved challenging (see SI for details).
Multiple conditions were screened for the desired esterifica-
tion, most providing the C12 ester as the sole or major
product, and a double-esterification product was not found.
Eventually, a process was established to produce the desired
C13 ester 24 involving the slow addition of isobutyryl chloride
and NEt3 to a preheated DCM solution of 22. The undesired
C12 ester 23 (23/24 = 1:1) was separated and treated with
K2CO3/MeOH to regenerate diol 22, which was suitable for
the esterification process again without further purification.
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Journal of the American Chemical Society
The desired C13 ester 24 was obtained in 77% overall yield
after 3 cycles. Next, classic benzoylation of 24 using BzCl or
Bz2O was attempted with various bases, solvents, and
temperatures. However, none of these conditions4 (see SI for
details) provided the desired benzoyl ester. Steric hindrance
around the C12 hydroxyl group appears to prevent the
benzoylation process. After extensive investigations, treatment
of 24 with BzOTf16 and pyridine at 60 °C gave the desired
C12 benzoyl ester in 83% yield. It is worth mentioning that if
the C12 hydroxyl group in 22 was benzoylated first it would
completely prevent the subsequent esterification of C13
hydroxyl group.
Lastly, the Bn group in 22 was removed by hydrogenation,
followed by DMP oxidation in one pot to give 1 in 86% yield,
completing the total synthesis of (+)-pedrolide. The analytical
data (1H NMR, 13C NMR, HRMS, and optical rotation) for 1
were in agreement with the data reported for the isolated
material. It is worth noting that over 200 mg of (+)-pedrolide
(1) was synthesized by this approach, demonstrating its
reliability.
In summary, we have achieved an asymmetric total synthesis
of pedrolide, which has an unprecedented [5−5−5−6−6−3]
hexacyclic core from a commercially available trans-p-
methoxycinnamaldehyde.17 The synthetically challenging
bicyclo[2.2.1] skeleton of pedrolide was efficiently installed
by an enantioselective ene reaction of cyclopentadiene and
trans-p-methoxycinnamaldehyde followed by a Wittig reaction
and a diastereoselective IMDA reaction cascade. The highly
functionalized carane ring system was synthesized via an RCM
reaction, followed by an uncommon free carbene cyclo-
propanation reaction. This will provide a new approach for
efficient and diastereoselective synthesis of the highly oxy-
genated carane ring system which is usually found in numerous
tigliane type natural products.1b Notably, the 12 contiguous
stereocenters of pedrolide including three quaternary stereo-
centers18 were constructed diastereoselectively and efficiently.
Furthermore, over 200 mg of (+)-pedrolide (1) was provided
by our total synthesis, demonstrating the scalability of our
synthetic route.19
■
*
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.3c14150.
Detailed experimental procedure, 1H NMR and 13C
NMR spectra, as well as X-ray data information (PDF)
Accession Codes
CCDC 2312696, 2312891, and 2312894 contain 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 Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
■ AUTHOR INFORMATION
Corresponding Author
Chuang-Chuang Li − Shenzhen Grubbs Institute, Department
of Chemistry, Guangming Advanced Research Institute,
Southern University of Science and Technology, Shenzhen
518055, China; Shenzhen Bay Laboratory, Shenzhen
D https://doi.org/10.1021/jacs.3c14150
pubs.acs.org/JACS Communication
518132, China; orcid.org/0000-0003-4344-0498;
Email: ccli@sustech.edu.cn
Authors
Wen Zhang − Shenzhen Grubbs Institute, Department of
Chemistry, Guangming Advanced Research Institute,
Southern University of Science and Technology, Shenzhen
518055, China; orcid.org/0000-0003-4504-7438
Peng-Cheng Yu − Shenzhen Grubbs Institute, Department of
Chemistry, Guangming Advanced Research Institute,
Southern University of Science and Technology, Shenzhen
518055, China
Chen-Yun Feng − Shenzhen Grubbs Institute, Department of
Chemistry, Guangming Advanced Research Institute,
Southern University of Science and Technology, Shenzhen
518055, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.3c14150
Author Contributions
#
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
This paper is dedicated to Professor Erick M. Carreira on the
occasion of his 60th birthday. This work was supported by the
National Natural Science Foundation of China (Grant no.
22101121 and 22225102), National Key R&D Program of
China (No. 2022YFE0205500), Shenzhen Bay Laboratory
(SZBL2021080601005 and Shenzhen Bay Scholars), and the
Shenzhen Science and Technology Innovation Committee
(JCYJ20220818100603008, JCYJ20210324104408023).
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