Enantioselective Total Syntheses of Pallambins A–D

Article abstract of DOI:10.1002/anie.201907523

The first enantioselective total syntheses of (?)-pallambins A–D have been achieved in 15 or 16 steps from a known chiral cyclohexenone. Salient features of the syntheses include a palladium-catalyzed oxidative cyclization to assemble the [3.2.1]bicyclic moiety, an Eschenmoser–Claisen rearrangement/lactone formation sequence to construct the C ring, an intramolecular Wittig reaction to form the D ring, and individual transformations of pallambins C and D to generate pallambins A and B. The described synthesis avoids protecting-group manipulations through the design of highly chemo- and stereoselective transformations. During the course of this work, a palladium-catalyzed method for the dehydrobromination of α-bromoketones was developed, and the scope of this transformation was also investigated.

Full text of DOI:10.1002/anie.201907523

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Accepted Article
Title: Enantioselective Total Syntheses of Pallambins A-D
Authors: Yanxing Jia, Xiwu Zhang, Xinxian Cai, Bin Huang, Lei Guo,
and Zhongrun Gao
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10.1002/anie.201907523
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Enantioselective Total Syntheses of Pallambins A-D
Xiwu Zhang, Xinxian Cai, Bin Huang, Lei Guo, Zhongrun Gao, and Yanxing Jia*
Abstract: The first enantioselective total syntheses of pallambins A-
D have been achieved in 15 or 16 steps from known chiral
cyclohexenone. Salient features of the work include a Pd-catalyzed
oxidative cyclization to assemble the [3.2.1]-bicyclic moiety, an
Eschenmoser-Claisen rearrangement/lactone formation sequence to
construct the C ring, an intramolecular Wittig reaction to form the D
ring. The described synthesis avoids protecting-group manipulations
by designing highly chemo- and stereoselective transformations.
During the course of this work,
a Pd-catalyzed method for
dehydrobromination of –bromoketones was developed.
Since 1994, a group of extraordinary complex diterpenes with the
common fused furofuranone rings have been isolated and
characterized from the liverworts, such as pallavicinin (1),
neopallavicinin (2), and pallambins A-D (3-6) (Figure 1A).[1-3] They
contain 4-6 congested rings and 7-10 contiguous stereocenters
including 1-2 all-carbon quaternary centers, representing
formidable challenges for the total synthesis. However, this family
of natural products exhibit no significant bioactivity,[2b] perhaps
due to their scarce availability from natural sources that has
limited their biological evaluation. Thus, the development of
concise chemical synthesis of these diterpenoids can improve the
availability of these molecules for full biological evaluation.
A plausible biosynthetic pathway for these natural products was
proposed by Asakawa (Figure 1A).[3] The cleavage of C7-C8 bond
of the labdane-type diterpenoid provides the common precursor
7. 1 and 2 arise through the reconstruction of C2-C8 bond via an
intramolecular aldol reaction. 3 and 4 are formed through
demethylation followed by the C4-C8 bond reconstruction. Lou
and coworkers have further demonstrated the photoinduced
interconversion of 3 and 4 to 5 and 6 through a diradical
rearrangement procedure.[2c]
The unprecedented and challenging molecular architectures of
1-6 have attracted considerable attention from synthetic
chemists.[4-8] The group of Wong pioneered the first total
syntheses of (±)-1 to (±)-4 from the Wieland-Miescher ketone.[5a,b]
Carreira and coworkers have achieved the first total syntheses of
(±)-5 and (±)-6 by the use of pentafulvene in an unprecedented
Diels-Alder reaction in 2015.[6] In the same year, we have
accomplished the first enantioselective syntheses of ()-1 and (+)-
2 from the known chiral cyclohexenone 8 (Figure 1B).[7] In 2016,
the Baran group reported an elegant approach to (±)-3 and (±)-4
without any protecting-group manipulations.[8]
Figure 1. (A) Structures of pallavicinin, neopallavicinin, and pallambins A-D as
well as their possible biosynthesis. (B) Our synthetic plan.
Encouraged by our recent success in the total synthesis of ()-
1 and (+)-2 from 8 and the aforementioned biogenetic hypothesis,
we envisioned that 8 could serve as the common intermediate
(corresponding to 7) for the synthesis of 1-6 (Figure 1).
Compound 8 could be easily transformed to 12, which undergoes
a Pd-catalyzed oxidative cyclization to afford the [3.2.1] bicyclic
ketone 13. Ketone 13 could be converted to 3-6 (Figure 1B). Thus,
we could achieve the divergent synthesis of 1-6 in a bioinspired
manner.[9] Herein we report the first enantioselective total
syntheses of pallambins A-D (3-6) without the use of protecting
groups.
Our retrosynthetic analysis of 3-6 is illustrated in Scheme 1. We
envisioned that 5 and 6 could be readily accessed through Lou’s
photoinduced interconversion of 3 and 4. In turn, 3 and 4 could be
generated from tetracycle 14, in which BCD three different ring
systems are forged featuring three different cyclizations. Thus, D-
ring is constructed by an intramolecular Wittig reaction from
[a]
[b]
X. Zhang, X. Cai, B. Huang, L. Guo, Z. Gao, and Prof. Y. Jia
State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmaceutical Sciences,
Peking University,
Xue Yuan Rd. 38, Beijing 100191, China
E-mail: yxjia@bjmu.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201907523
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lactone 15. The C-ring is forged by lactone formation from amide
16. Amide 16 could be generated via a Claisen rearrangement of
the allylic alcohol 17 which could be readily prepared from bicycle
13. Bicycle 13 could be accessed from 8 (Figure 1B).
followed by addition of Davis oxaziridine (20) provided the -
hydroxylactone 21 as a single stereoisomer.[13] Owing to the
highly constrained caged structure of 19, the hydroxylation only
occurred on the less hindered convex face, syn to the C8 methyl
group. This is opposite to the stereochemistry required for the
natural products. Thus, the inversion of the configuration of C11
hydroxyl group was performed by an oxidation/reduction strategy.
Oxidation of 21 with DMP afforded the corresponding ketolactone
which was subsequently underwent a complete chemo- and
stereoselective reduction with LiAlH(Ot-Bu)3 to give the desired
alcohol 15 as a single stereoisomer in 99% yield.
With tricycle 15 in hand, the last ring was introduced. Heating
15 with (triphenylphosphoranylidene)ketene in m-xylene at 160 oC
accomplished the acylation of the -hydroxyl group and
subsequent intramolecular Wittig reaction to afford tetronic ester
22.[14] It is worth to note that the reaction temperature and the
reaction time was critical for the high yield. Higher temperature
and longer reaction time resulted in lower yield. Chemo- and
stereoselective reduction of the tetronic ester double bond was
then pursued. After extensive experimentation, we were delighted
to find that reduction of 22 with CuH, generated in suit by reaction
of CuI with Red-Al, provided the desired 14 in 94% yield.[15] The
structure of 14 was verified by X-ray crystallography.[16]
At this stage, we needed to install C1,C2 double bond;[17]
however, it proved exceptionally challenging. The one-step
methods for direct dehydrogenation of ketones were investigated
firstly. However, oxidation of ketone 14 with IBX,[18] and other
methods such as Pd-catalyzed dehydrogenation did not give any
24.[19,20] Thus, the two-step methods, such as silyl enol
ethers/Saegusa reaction,[21] selenoxide and sulfoxide elimination
reactions,[22,23] as well as bromination/dehydrobromination, were
tested.[24] However, attempts to prepare the corresponding silyl
enol ether and to introduce phenylselenide and phenylsulfide also
failed. Gratefully, bromination of 14 with Py·HBr3 in HOAc gave
23 in 80% yield as a single stereoisomer.[25] Attempts to
dehydrobromination of 23 with Li2CO3/LiBr, DBU or other bases
were screened. The reaction did not occur at low temperature (<
80 oC), and the starting material was decomposed at high
temperature (> 80 oC) and no desired product 24 was observed.
These results indicated that 23 and(or) 24 might be sensitive to
the bases at high temperature. Thus, a mild dehydrobromination
method needed to be developed.
Inspired by the mild reaction conditions and reaction
mechanism of Pd-catalyzed Heck reaction, we envisioned that
oxidative addition of the –bromoketone 23 to Pd(0) species
could give the corresponding alkylpalladium species, which
undergoes β–hydride elimination to provide the desired enone 24.
With this idea in mind and after extensive experimentation (the
detailed information see SI), we found that treatment of 23 under
the optimized conditions (Pd(OAc)2, PPh3, and Et3N in DMSO)
afforded the desired product 24 in 41% yield and the Heck-type
product 25 in 38% yield. Installation of the ethylidene group on 24
provided the target molecule pallambin C (3) in 30% yield and
pallambin D (4) in 51% yield. The physical data of our synthesized
products 3 and 4 are identical to those reported in the
literature.[1,2,5b,8]
Scheme 1. Retrosynthetic analysis of pallambins A-D (3-6).
Our synthesis commenced with the known chiral 8 which could
be readily prepared in 84% ee following the Stoltz’s procedure
(Scheme 2).[10] Conjugate addition of a vinyl group to 8 followed
by methylation afforded the ketone 11 with a diastereomeric ratio
(dr) of 3:1 at C5. Treatment of ketone 11 with Et3N and TBSCl led
to the corresponding thermodynamic TBS enol ether, which was
subjected to our optimized Pd-catalyzed oxidative conditions to
give the desired bicyclo[3.2.1]octane system 13 in 64% yield.[7]
Chemoselective epoxidation of electron-rich double bond of 13
with m-CPBA gave the corresponding epoxide, which was
subsequently treated with PTSA in the presence of 1,3-
dimethylimidazolidin-2-one (18) to provide the desired allylic
alcohol 17.[11]
With a robust route to 17, we focused on the construction of C-
ring. Heating 17 and N,N-dimethylacetamide dimethyl acetal in
toluene at 115 °C afforded the desired γ,δ-unsaturated amide 16
in 88% yield as a single diastereomer.[12] The remarkable
stereoselectivity can be easily explained that the Claisen
rearrangement would preferentially occur on the less sterically
hindered exo-face. Treatment of 16 with H2SO4 in refluxing
ethanol provided lactone 19 in 84% yield.
In order to install the hydroxyl group at C11, the ketone of 19
had to be protected. However, further visual inspection of the
molecular models indicated that the free C3 ketone group might
not affect the -hydroxylation due to the sterically congested A/B
ring system shielding α-position of C3 ketone group. Therefore,
we audaciously opted to introduce the C11 hydroxyl group directly
without protection of C3 ketone. After testing several conditions,
we found that deprotonation of 19 with 3 equivalents of LiHMDS
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10.1002/anie.201907523
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Scheme 2. Total syntheses of pallambins A-D (3-6). HMPA=hexamethylphosphoric triamide, TBS=tert-butyldimethylsilyl, DMSO=dimethyl sulfoxide, m-CPBA=
meta-chloroperoxybenzoic acid, PTSA=p-toluenesulfonic acid, LiHMDS=lithium hexamethyldisilazide,THF=tetrahydrofuran, DMP=Dess-Martin periodinane, Red-
Al=sodium bis(2-methoxyethoxy)aluminumhydride, Ms = methanesulfonyl, DMAP = 4-dimethylaminopyridine.
Finally, we sought to convert pallambins C (3) and D (4) to
pallambins (5) and B (6) under UV light according to Lou’s
research.[2c] Interestingly, we serendipitously discovered that
individual irradiation of 3 and 4 under milder conditions (UV lamp,
8W) in CH2Cl2 at 25 oC afforded 5 and 6, respectively, without the
cis/trans isomerization at ∆13(14) between 5 and 6 as well as 3 and
4. This result clearly indicated that the diradical rearrangement
Table 1: Scope of dehydrobromination reaction.[a,b]
require lower energy than the cis/trans isomerization at ∆13(14)
.
The physical data of our synthesized products 5 and 6 are
identical to those reported in the literature.[2,6]
As depicted in Table 1, this Pd-catalyzed dehydrobromination
method proves to be general. Both cyclic and acyclic systems can
be employed as the substrates to give ,β-unsaturated carbonyl
compounds. Notably, the Pd-catalyzed enone formation under
mild conditions should be valuable to synthetic community, which
is difficult to achieve by other means (Supporting Information).
[a] Reaction conditions: 26 (0.5 mmol), Pd(OAc)2 (0.15 mmol), PPh3 (0.30
mmol), Et3N (2.50 mmol) in DMSO (10 mL). [b] Isolated yield was given. [c]
Pd(OAc)2 (0.10 mmol) was used. [d] Pd(OAc)2 (0.05 mmol) was used.
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In summary, we have accomplished the first asymmetric total
syntheses of pallambins A-D in 15-16 steps from the known
cyclohexenone 8 without the use of protecting groups. The
success of this protecting-group-free synthesis was mainly
dependent on several highly chemo- and stereoselective
reactions.[26] The present synthesis features a Pd-catalyzed
oxidative cyclization to assemble the [3.2.1]-bicyclic moiety, a
Claisen rearrangement/lactone formation sequence to construct
the C ring, an intramolecular Wittig reaction to form the D ring.
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Acknowledgements
This research was supported by the National Natural Science
Foundation of China (21572008) and the Drug Innovation Major
Project (Grant No. 2018ZX09711-001-005-005).
Keywords: diterpenoids • palladium • protecting-group-free •
total synthesis • natural products
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COMMUNICATION
Layout 2:
COMMUNICATION
Xiwu Zhang, Xinxian Cai, Bin Huang, Lei
Guo, Zhongrun Gao, and Yanxing Jia*
Page No. – Page No.
Enantioselective Total Syntheses of
Pallambins A-D
The first enantioselective total syntheses of pallambins A-D has been achieved
without the use of protecting groups. Salient features of the work are the formation
of three rings via three cyclizations. A palladium-catalyzed method for
dehydrobromination of –bromide ketone was developed.
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