Enantioselective Total Synthesis of (+)-Plumisclerin A

Article abstract of DOI:10.1002/anie.201808517

The first and enantioselective total synthesis of (+)-plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring-formation protocol was adopted to generate the c

Full text of DOI:10.1002/anie.201808517

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Accepted Article
Title: Enantioselective Total Synthesis of (+)-Plumisclerin A
Authors: Ming Gao, Ye-Cheng Wang, Kai-Rui Yang, Wei He, Xiao-
Liang Yang, and Z.-J. Yao
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808517
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10.1002/anie.201808517
Angewandte Chemie International Edition
Accepted Article
COMMUNICATION
Enantioselective Total Synthesis of (+)-Plumisclerin A
Ming Gao,[a] Ye-Cheng Wang,[a] Kai-Rui Yang,[a] Wei He,[b] Xiao-Liang Yang,[a] and Zhu-Jun Yao[a]*
Dedicated to Professor Yu-Lin Wu on the occasion of his 80th birthday
Abstract: The first and enantioselective total synthesis of (+)-
plumisclerin A, a novel unique complex cytotoxic marine diterpenoid,
has been accomplished. Around the central cyclopentane anchorage,
a sequential ring-formation protocol was adopted to generate the
characteristic tricycle[4.3.1.01,5]decane and trans-fused dihyrdopyran
moiety. Scalable enantioselective La(III)-catalyzed Michael reaction,
palladium(0)-catalyzed carbonylation and SmI2-mediated radical
conjugate addition were successfully applied in the synthesis,
affording multiple grams of the complex and rigid B/C/D-ring system
having six continuous stereogenic centers and two all-carbon
quaternary centers. The trans-fused dihyrdopyran moiety with an
exo side-chain was furnished in final stage through sequential redox
transformations from a lactone precursor, which overcome the
largish steric strain of the dense multiring system. The reported total
synthesis also confirms the absolute chemistries of natural (+)-
plumisclerin A.
Since the isolation of xenicin (Fig. 1, 1), the first xenicane
diterpenoid from the soft coral Xenia elongate in 1977,[1] more
than a hundred diverse members have been discovered in this
family. A cyclononane ring and an isoprenyl side chain, or their
diverse modification forms, are characteristic structural features
for all the xenicanes.[2] This family of marine products were also
reported to display a wide range of biological activities, such as
cytotoxic, antibacterial and antitumor activities.[2] Unfortunately,
to date, only few total syntheses have been reported.[3]
Figure 1. A) Possible biosynthetic pathway to plumisclerin A (4); and B)
general consideration of sequential ring-formation based on a multi-substituted
Plumisclerin A, a new unique member of this family, was
recently isolated and characterized by Reyes and co-workers
from the cytotoxic crude extracts of soft coral Plumigorgia
terminosclera in 2010, showing low-micromolar cytotoxicity
against multiple tumor cells, such as A549 cells (GI50 of 4.7 μM),
HT29 cells (GI50 of 2.1 μM) and MDA-MB-231 cells (GI50 of 6.1
μM).[4] Compared to other xenicane members, plumisclerin A is
structurally more complex, featuring a compact tetracyclic
(6/5/4/6-fused ring) system. This brand-new terpene carbon-
skeleton is newly named as plumisclerane (5, Fig. 1A).
Plumisclerin A was proposed to be biogenetically transformed
from cristaxenicin A (6/9-fused ring system, 2, Fig. 1A), a known
xenicane, through an intramolecular [2+2] cycloaddition
cyclopentane (ring B) anchorage.
(3, Fig. 1A).[4,5] However, the absolute stereochemistry of
plumisclerin A remains unconfirmed yet.
Existence of an unusual tricyclo[4.3.1.01,5]decane with high
congestion and rigidity makes plumisclerin A an attractive
synthetic target. The complex 5/4/6-ring system including a fully
substituted and two quaternary carbon centers bridged
cyclobutane (C ring) and seven continuous stereocenters renders
it many predictable and unpredictable challenges for chemical
synthesis. An additional synthetic difficulty lies in the dihydropyran
ring (ring A) with an exo-side chain, which is trans-fused to the
central cyclopentane. For the sp2 hybrid nature of both C3 and C4
will make the whole skeleton to be further rigid and higher
tension. In the past four decades, the synthesis of xenicane
diterpenoid having such a trans-fused unsaturated pyranoside
moiety has proven to be difficult and has not been realized
yet.[2,3,6] Herein, we report the first and enantioselective total
synthesis of natural (+)-plumisclerin A, as well as confirmation of
the absolute stereochemistry.
[a]
M. Gao, Y.-C. Wang, K.-R. Yang, Dr. W. He, Prof. Dr. X.-L. Yang,
and Prof. Dr. Z.-J. Yao
State Key Laboratory of Coordination Chemistry, and Jiangsu Key
Laboratory of Advanced Organic Materials
School of Chemistry and Chemical Engineering
Nanjing University
163 Xianlin Avenue, Nanjing, Jiangsu 210023, CHINA
E-mail: yaoz@nju.edu.cn
Structural perspective of plumisclerin A reveals that
cyclopentane (ring B) is located at the center of the molecule.
Therefore, the common cyclopentane could be devised as an
anchorage to support sequential formation of other rings (I, Fig
1B), such as construction of the complex 6/5/4/6- tetracyclic
framework (6, Fig 1B) and generation of trans-fused dihydropyran
[b]
Dr. W. He
STA Pharmaceutical Co. Ltd.
90 Delin Road, Waigaoqiao, Shanghai, China
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.201808517
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COMMUNICATION
Figure 2. Retrosynthetic analysis of plumisclerin A (4).
moiety via proper redox sequence.[7,8,9] Based on such
Scheme 1. Scalable enantioselective synthesis of cis-bicyclic ketone 9.
considerations, plumisclerin
A (4) can be retrosynthetically
simplified to a trans-lactone 6 (including all rings) by functional
group manipulations (Fig 2). Lactone 6 is then disassembled into
tricyclo[4.3.1.01,5]decane
system
7.
A
SmI2-mediated
membered ring is the first ring docked to the central cyclopentane.
Complete reduction of the diester 16 was carried out with LiAlH4,
and the resulting 1,3-diol was selectively protected with 2,2-
dimethoxypropane. Dess-Martin oxidation of the remaining
alcohol provided enone 17 (78% overall yield, 3 steps from 16),
whose absolute stereochemistry was confirmed by the
corresponding X-ray single crystallographic analysis. Catalytic
hydrogenation of 17 was carried out in the presence of 10% Pd/C
and NaHCO3 in MeOH, affording the cis-bicyclic ketone 9 in 83%
yield.
Diastereoselectivity of the C4a-alkylation of ketone 9 is crucial
to late-stage establishment of the trans-fused dihyrdopyran ring.
To our delight, reaction of the enolate prepared from bicyclic
ketone 9 with methyl bromoacetate 18 afforded ketone 19 in 90%
yield, as a single diastereoisomer with desired stereochemistry
(Scheme 2). Treatment of sodium enolate derived from 19 with
PhNTf2 followed by Pd(0)-catalyzed carbonylation (cat. Pd(PPh3)4,
CO, MeOH, DMF)[12] provided unsaturated esters 20 (51%
yield for 2 steps; 98% ee by chiral HPLC). Comparison to that
with NaHMDS, use of either LiHMDS or KHMDS in this reaction
resulted in poor regioselectivities in the enolization of ketone 19.
Then, the O,O-acetonide protecting group of 20 was removed
under acidic conditions, and one primary alcohol at C19 was
regioselectively protected with TBSCl, giving mono-silyl ether 21
(80% yield for 2 steps). Oxidation of the remaining alcohol 21 with
pyridinium chlorochromate (PCC) provided aldehyde 8 (99%
yield), the precursor for constructing the rigid tricyclodecane
system. A SmI2-mediated ketyl radical 1,4-addition[6,13] was
intramolecular radical conjugate addition could be exploited to
form cyclobutanol 7.[6] Compound 8 could be prepared from the
corresponding ketone precursor 9 through introduction of the two-
carbon substituent at the C4a position, and Pd-catalyzed
carbonylation. Cyclic ketone 9 is traced back to cyclopent-2-en-1-
one 10 (origin of the cyclopentane anchorage), malonate 11 and
bromide 12 by enantioselective La-catalyzed Michael reaction[10]
and intramolecular aldol reaction. We hypothesized that the
absolute configuration of the C6 of plumisclerin A is S, based on
its biogenetic relationship with cristaxenicin A (Fig 1A).[5a]
The first task of this total synthesis is to achieve and scale up
the asymmetric synthesis of tricyclo[4.3.1.01,5]decane core 22
(Schemes 1 and 2). As shown in scheme 1, based on the work of
Shibasaki,[10] the first stereogenic center was enantioselectively
introduced by catalytic asymmetric conjugate addition of malonate
13[11] to cyclopentenone 10 with the catalysis of (S,S)-La-bis-
BINOL 14 (10 mol%).[10] Our procedure could reliably provide the
adduct (S)-15 on a reasonably large scale (26 g of 10/batch, 67%
yield, and >98% ee by HPLC). It is noteworthy that the rare-earth
catalyst, (S,S)-La-bis-BINOL 14, could be recovered and re-
applied to the same reaction for two additional times (totally three
times), providing (S)-15 with comparable enantiomeric purity (see
Supporting Information for more details). Ozonolysis of the
terminal olefin 15 followed by intramolecular aldol reaction and
dehydration in the presence of catalytic amount of p-TSAH2O
furnished enone 16 in 63% yield, in which the newly formed six-
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10.1002/anie.201808517
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COMMUNICATION
Scheme 3. Protocols to construct dihydropyran ring trans-fused to the central
cyclopentane.
Scheme 2. Gram-scale synthesis of tricyclo[4,3,1,01,5]decane intermediate 22.
and II seem to be more direct, formation of the strained trans-
dihydropyran moiety (A ring) is exceptionally challenging under
non-biogenetic conditions.[8,9] The X-ray analysis of diester
intermediate 7 (Scheme 2) also showed that the torsion angle of
the two adjacent branches (at C4a and C11a positions,
respectively) was spatially unfavorable for the expected ring-
closure. Indeed, we failed to convert diester 7 to the
corresponding dihydropyrans either by protocol I or II. To resolve
the above obstacle, an indirect approach based on a
lactonization (protocol III) was then taken into our consideration.
Treatment of 7 with LDA and methyl bromoacetate afforded
malonate 29 (74% yield) chemoselectively.[14] Selective
reduction of malonate 29 was accomplished with DIBAL-H at
employed to establish the tricyclodecane system, and the final
optimized ratio of 22 and 23 (dr at C11a) was improved up to
3.3:1 on a multi-gram scale, using SmI2 (5 equiv.) and HMPA (15
o
equiv.) in THF and t-BuOH (10:1, v/v) at −78 C. This reaction
generated three new continuous stereogenic centers at C11a,
C11 and C12. It is believed that the diastereoselectivity at C11a
would be influenced by temperature and proton source (see
Supporting Information for more details). In addition, formation of
the cyclobutane pushes the D-ring to adopt a high-energy boat
conformation, according to the X-ray analysis of a following
intermediate 7 (Scheme 2). Unfortunately, our attempts to convert
the undesired diastereomer 23 into 22 all failed under a variety of
alkaline conditions, leading to some kinds of unclear
fragmentations. The newly born hydroxyl group at C12 of 22 was
then protected with TBSOTf and Et3N, affording diester 7 in 91%
yield.
o
−40 C.[15] The favorable feature of diol 30 is that one alcohol
can be applied to construct A ring, and the other can be
employed to install the side-chain branch later. Following this
idea, diol 30 was converted into the corresponding lactone with
a catalytic amount of CSA,[16] and the remaining hydroxyl group
was protected with TESOTf to provide stable tetracyclic lactone
31 in 55% yield (2 steps). Sequential redox transformation of
lactone 31 into plumisclerin A was then executed (Scheme 4).
With multiple-gram quantity of diester 7 in hand, we began to
investigate the final ring formation, a dihydropyran trans-fused to
the cyclopentane. Several protocols were attempted based on
intermediate 7 (protocols I, II, III, Scheme 3). Though protocols I
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10.1002/anie.201808517
Angewandte Chemie International Edition
COMMUNICATION
by the spatial environment of 33. Oxidative elimination of seleno
compound 36 furnished the desired α,β-unsaturated aldehyde
38, which bears a further strained molecule skeleton. While, the
parallel oxidative elimination of the other seleno product 35
delivered 37 only, whose double bond is located between C4
and C4a by following general oxidative syn-elimination
mechanism.[22] In order to save the material, the undesired
seleno-product 35 was recycled back to aldehyde 33 (64% yield)
by reduction with tributyltin hydride in the presence of
azobisisobutyronitrile (AIBN) in toluene at 110 °C.[23]
Introduction of the isopentyl group into enal 38 failed when the
moderately reactive isopentyl cerium reagents was employed.[24]
After a number of screenings, the 1,2-addition to enal 38 was
o
smoothly carried out with isopentyl Grignard reagents at −78 C.
The resulting allylic alcohol was oxidized with Dess-Martin
periodinane to yield α,β-unsaturated ketone 39. Finally,
complete removal of O-silyl ethers of 39 with 70% HF-pyridine[25]
followed by full O-acylation with acetic anhydride and DMAP
delivered (+)-plumisclerin A (4) in 87% yield (98% ee by chiral
HPLC). The NMRs, HRMS, IR, and optical rotation (synthetic:
[]D 105.3; natural: []D 125.0) of our synthetic sample were in
well agreement with those reported for natural product.[4]
Completion of the first catalytic enantioselective total synthesis
of (+)-plumisclerin A also enabled us to unambiguously confirm
the absolute chemistry of natural compound as (1R,4aS,6S,7R,
11S,11aR,12S). It’s noteworthy here that this synthesis is also
the first example for plumisclerane marine diterpenoids (Fig 1, 5).
In summary, the first and enantioselective total synthesis of
(+)-plumisclerin A, a challenging cytotoxic marine diterpenoid
containing a novel rigid multiring carbon-skeleton, has been
achieved in 27 longest linear steps.
A sequential ring-
construction protocol geometrically supported by the central
cyclopentane was performed in the total synthesis. Successful
application of scalable La(III)-catalyzed enantioselective Michael
reaction and diastereoselective intramolecular SmI2-mediated
ketyl radical conjugate addition enabled multiple gram
preparation of the complex rigid tricyclo[4,3,1,01,5]decane core.
Internal lactionization provided a practical way to furnish the
trans-fused dihydropyran moiety, leading to final completion of
the total synthesis. The reported total synthesis is believed to
provide an entrance to novel medicinally interesting complex
derivatives of marine xenicanes, and opens new opportunities
for the related biological investigations.
Scheme 4. Completion of the total synthesis of (+)-plumisclerin A.
Reduction of lactone 31 followed by O-acylation afforded acetal
32 (75% yield, 3:1 dr at C1). Removal of TES group followed by
Swern oxidation[17] of the resulting alcohol (at C13) furnished
aldehyde 33 in 78% yield in one pot. The subsequent
introduction of a C=C bond to aldehyde 33, between C3 and C4,
was proven to be very troublesome. Because of its highly rigid
structure, such an operation upon 33 has to overcome much
higher energy barrier. Indeed, formation of the double bond
failed by direct oxidations such as IBX oxidation[18] and Saegusa
oxidation.[19] Meanwhile, it also failed to form -seleno product
using classical conditions (M+HMDS with PhSeX, silyl enol ether
with PhSeX and piperidine with PhSeX).[20] Finally, L-
prolinamide-promoted -selenenylation of aldehyde 33 was
found to work well when N-(phenylseleno)phthalimide 34 was
used as the seleno reagent.[21] The reaction was carried out with
L-prolinamide (1.2 eq.) and 34 (5 eq.), affording two separable
seleno diastereomers 35 and 36 (80% yield, 2.5:1 dr). To our
Acknowledgements
This project is financially supported by National Key Research
and Development Program of China (No. 2018YFC0310900),
National Natural Science Foundation of China (No. 21532002,
21761142001), and the Fundamental Research Funds for the
Central Universities (No. 020514380131). The authors also
thank Drs. Zhenyu Yang and Ji-Peng Chen (SIOC), and Prof.
Shaozhong Wang (NJU) for their early efforts and helpful
discussions to this work.
surprise, alternative use of D-prolinamide gave
a similar
diastereoselectivity for the two seleno-products. The
diastereoselectivity of this reaction seems to be highly controlled
Keywords: plumisclerin A • total synthesis • conjugate addition •
samarium diiodide • scalable enantioselective synthesis
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Entry for the Table of Contents (Please choose one layout)
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Ming Gao, Ye-Cheng Wang, Kai-Rui
Yang, Wei He, Xiao-Liang Yang, and
Zhu-Jun Yao*
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Enantioselective Total Synthesis of
(+)-Plumisclerin A
Text for Table of Contents
The first and enantioselective total synthesis of (+)-plumisclerin A, a cytotoxic
complex marine diterpenoid featuring with a brand-new unique carbon-skeleton of
highly strained tricycle[4.3.1.01,5]decane, has been accomplished. A sequential
ring-formation protocol was employed using the central cyclopentane as the
anchorage, and scalable enantioselective La(III)-catalyzed Michael addition, Pd(0)-
catalyzed carbonylation and SmI2-mediated intramolecular radical conjugate
addition successfully served as the key reactions in this synthesis.
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