An Enantioconvergent and Concise Synthesis of Lasonolide A

Article abstract of DOI:10.1002/anie.201811093

Efficient access to medicinally significant natural products is an essential basis for the development of pharmaceuticals. The limited availability of marine natural products impedes broad biological evaluation. Despite several elegant syntheses of (?)-lasonolide A having been reported, a practical synthesis of this potent anticancer polyketide remains elusive. Based on the application of borane as a traceless protecting group and the development of an unprecedented bissulfone reagent for Julia olefination, (?)-lasonolide A was assembled in an enantioconvergent manner through the application of stereoselective hydroboration, allylation, and oxidation. This concise route may provide a realistic solution for accessing derivatives and analogues.

Full text of DOI:10.1002/anie.201811093

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Accepted Article
Title: Enantioconvergent and Concise Synthesis of Lasonolide A
Authors: Ran Hong, Lin Yang, Zuming Lin, Shunjie Shao, and Qian
Zhao
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811093
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Enantioconvergent and Concise Synthesis of Lasonolide A
Lin Yang, Zuming Lin, Shunjie Shao, Qian Zhao, and Ran Hong*
Abstract: Efficient access to medicinally significant natural product is
an essential basis for the development of pharmaceuticals. The
limited availability of marine natural products impedes broad biological
evaluation. Despite several elegant syntheses of (-)-lasonolide A
having been reported, a practical synthesis of this potent anticancer
polyketide remains elusive. Based on application of borane as a
traceless protection and development of an unprecedented bissulfone
reagent for double Julia olefination, (-)-lasonolide A was assembled
in an enantioconvergent manner by an array of stereoselective
hydroboration, allylation, oxidation, and oxa-Michael cyclization. This
compatibility of borinate 2 with chemical transformations. As a
proof of the concept, we devised an efficient synthesis of
antitumor marine polyketide lasonolide A (4) with the capacity of
alkylborane as traceless protecting group.
Lasonolide A (4) was identified by McConnell and co-workers
from a Caribbean orange-red marine sponge, Frocepia sp.
(Scheme 2A).[7] The complex macrolide exhibited promising
activities for the treatment of pancreatic cancer with a distinct
mode of action (MOA) from most other cancer drugs, which
highlights its potential as a valuable drug in the treatment of multi-
drug resistance cancer cell lines.[8] The biological profile as well
as its unique chemical structure render the polyene macrolide an
intriguing target for the synthetic community.[9] Despite many
complex marine natural products are identified as promising drug
leads,[10] harvesting from vulnerable marine resources becomes
unsustainable.[11] Development of scalable synthetic route with
feasible operations remains a high demand.
concise route may provide
derivatives and analogs.
a realistic solution for accessing
Hydroboration of alkene and subsequent oxidation are widely
adopted protocols in organic synthesis since the generalization
six decades ago.[1] The oxidation step-derived borinate 2 was
generally unstable and thus difficult for isolation (Scheme 1A).[2,3]
However, the diagonal element silicon-derived various silane
reagents are popularized as protecting groups for alcohol in
organic synthesis.[4] We envisioned that the lability of borinate 2
can be adopted as a tentative protection due to a rapid reaction
of borane with alcohol without interfering other functional groups
and feasible removal of boryl group during the work-up stage
(Scheme 1B). Given the stress of economics in organic
synthesis,[5] such protection strategy would diminish additional
reagents, waste disposal, and purification steps.[6] The additional
challenge for the boryl group as protection is that the mutual
Scheme 1. (A) Hydroboration/oxidation process; (B) Logic of protection design
with borane. FG = functional group.
[a]
Dr. L. Yang, Z. Lin, S. Shao, Prof. Dr. R. Hong
Key Laboratory of Synthetic Chemistry of Natural Substances,
Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032, PR China
E-mail: rhong@sioc.ac.cn
Scheme 2. (A) Synthetic design of lasonolide A (4); (B) Construction of the triol
moiety in the B-ring via iterative hydroboration-oxidation process; (C) Enzymatic
resolution of allenic alcohol (10). THP
= tetrahydropyran, BPS = tert-
butyldiphenylsilyl, PT = phenyl tetrazolyl, BT = benzothiazolyl, TBS = tert-
butyldimethylsilyl.
[b]
[c]
Dr. L. Yang, S. Shao, Prof. Dr. R. Hong
University of Chinese of Academy of Sciences
19A Yuquan Road, Beijing 100049, PR China
Dr. Q. Zhao
Jiangsu Key Laboratory of Chiral Drug Development, Jiangsu
Aosaikang Parmaceutical CO., LTD., Nanjing, 211112, PR China
Supporting information for this article can be found under: ((Please
delete this text if not appropriate))
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Scheme 3. (A) Synthetic route toward acid 21; (B) A possible stereochemical control for the hydroboration of borinate derived from 12. TBAOH =
Tetrabutylammonium hydroxide, CSA camphorsulfonic acid, DMP 2,2-dimethoxypropane, BAIB bis(acetoxy)-iodobenzene, TEMPO 2,2,6,6-
tetramethylpiperidine oxide, DIBAL-H = diisobutylaluminium hydride, Dess-Martin = Dess-Martin periodinane.
=
=
=
=
The logic of our modular approach is outlined in Scheme 2A,
involving a connection of two key tetrahydropyran fragments 5
and 6 through a double Julia olefination with bissulfone 7 and an
end-game macrolactonization. The remaining double bonds can
be installed by operationally feasible Wittig-type olefinations. For
tetrahydropyrans A and B, an enantio-divergent approach was
developed based on the hydroboration-allylation[12] and an
unprecedented iterative hydroboration-oxidation (Scheme 2B). In
this approach, two enantiomers derived from the enzymatic
kinetic resolution (KR) of racemic α-allenic alcohol[13] (Scheme
2C) are converted into the two individual fragments that are then
merged into the advanced intermediate at a later stage in the
synthesis.[14]
C11, our initial attempt at the hydroboration/oxidation afforded a
complex mixture including Z-to-E isomers of the alkene and a 1,4-
diol with uncertain stereochemistry at C10-Me due to the
reversibility of the hydroboration (Figure S5).[16,17] We envisioned
that a possible rigid conformation derived from the chelation of
alkylborane with the diol substrate might block the subsequent
stereoselective hydroboration due to the bulky group on the boron.
Alternative transition state via the Felkin-Ahn model proposed in
the reaction of the substrate with borane would favor the requisite
facial selectivity (Scheme 3B). After experimentation (Table S2),
9-BBN was first added to react with the primary alcohol of 12 (11B
NMR for the corresponding borinate at 56.4 ppm)[16] then an
excess of IpcBH2 was introduced to promote the hydroboration-
oxidation to generate syn,syn-triol 9 in good diastereoselectivity
(ds 6.4/1) and 70% isolated yield on a 2-gram scale.
The key element to introduce a hydroxy group at C11 in the B-
ring relies on the stereoselective hydroboration of the tri-
substituted alkene, which was derived from the first hydroboration
of the allene. α-Acetoxyl allene derivative (S)-11 was documented
as a poor substrate[15] for hydroboration due to the complicated
pathways to form various compounds, such as a diene, a 1,2-diol,
an E-1,4-diol, and a homoallylic alcohol (Figure S3 and Table
S1).[16] The dominant side product diene implicated competition
between 1,4-elimination and alkyl migration on to the boron. It was
found that a solution of tetrabutylammonium hydroxide (TBAOH)
and hydroperoxide was effective to directly deliver Z-alkene diol
12, indicating a preferable alkyl migration on to boron as well as
its dual role of hydrolyzing the acyl group. The enantiomeric
excess of the diol was further enriched up to >99% ee after
recrystallization (Scheme 3A). To install the secondary alcohol at
With the triol 9 in hand, subsequent protection and removal of
the silyl group was operated in “one-pot” to yield compound 13, in
which the primary alcohol was selectively oxidized and
subsequent Wittig reaction[18] gave the conjugated ester 14. Upon
treatment of para-chlorobenzenesulfonic acid (CBSA), the
cascade process including removal of ketal and oxa-Michael
cyclization[19] (6-exo) was realized to deliver cis-tetrahydropyran 6
in 82% yield. The following chain elongation at C12 was proposed
to adopt one-pot protocol of oxidation-olefination. However, it was
found that epimerization at C11 occurred during the oxidation of
the C12 primary alcohol with bis(acetoxy)iodobenzene (BAIB)
and TEMPO. Therefore, a series of TEMPO derivatives were
screened (Table S3) and 4-PhCO2-TEMPO[20] with BAIB provided
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Scheme 4. Synthetic route toward sulfone 31. TBA F= tetrabutylammonium fluoride, TMG = tetramethylguanidine, PTSA = para-toluenesulfonic acid, TEA =
triethylamine, TMS = trimethylsilyl.
the best isolated yield without considerable epimerization. The
subsequent reaction with Still-Gennari phosphonate 15
reaction, and acetalization occurred. The impressive high yield,
regioselectivity, and stereoselectivity in resultant 26 as well as the
complexity established in a tandem manner provide an efficient
solution for accessing such multi-centered tetrahydropyran (A
ring), which is superior to the reported sequences.[9]
[21]
furnished the trisubstituted cis-conjugated ester 16 in good yield
(Z/E 10/1). After silylation of C9-OH, chemoselective control of the
DIBAL-H reduction of the two esters could afford aldehyde 18 in
excellent yield (96%). Encouragingly, without further purification,
aldehyde 18 was suitable for the following Horner–Wadsworth–
Emmons (HWE) reaction with phosphate 19[22] to generate acid
20 after hydrolytic work-up (67% yield from 17). X-ray analysis[23]
further confirmed the requisite stereochemistry of the three
carbon-carbon double bonds, while the coupling pattern of the
vinylic protons in the NMR spectra of 20 were not conclusive.
Dess-Martin periodinane[24] readily promoted the oxidation of the
allylic alcohol to form Z-enone acid 21 in 94% yield.
After cleavage of the vinyl group by ozonolysis, subsequent
reduction and protection afforded silyl ether 27. The next step
would be removal of the benzyl group for the introduction of the
side chain. Although hydrogenolysis with 10% Pd/C was
convenient and gave a high yield of diol 5, we managed to devise
transition-metal-free conditions for the debenzylation. A lithium-
naphthalene system[28] was effective when the secondary alcohol
at C21 was protected by 9-BBN (11B: 56.7 ppm).[16] Without the
borane pretreatment, the silyl group was migrated to the C21-OH
to result in the reduced yield. The structure of the silyl-migrated
product 5a was further elucidated by X-ray analysis,[23] which also
confirmed the requisite stereochemistry of C19-C23 in the A-ring.
A gram-scale and chemoselective oxidation of the primary alcohol
and subsequent Wittig olefination with 28[9e] proceeded smoothly
to deliver advanced intermediate 29 in 70% yield with excellent Z-
selectivity (Z/E = >20/1). With trimethylsilyl triflate (TMSOTf) and
2,6-lutidine,[29] deacetalization readily occurred to release
aldehyde 30, and the C21-OH was protected in situ by the
trimethylsilyl group. The crude aldehyde was suitable for the
subsequent Julia olefination without further purification.[30]
Inspired by Kang’s iterative protocol by Julia reaction[9b] to merge
two aldehyde fragments, bissulfone 7 was designed to integrate
two highly functionalized aldehyde motifs and to avoid the
oxidation step of converting the second thioether to sulfone after
the first Julia olefination. After meticulous evaluation of the
reactivity of several sulfones (Figure S6 and Table S4), 7 was
treated with KHMDS to deprotonate the phenyl tetrazolyl (PT)
sulfone [31] preferentially. The generated anion was reacted with
Although a similar synthetic sequence was established in our
previous investigation,[12[ the A ring formation was planned
through another Michael addition. In contrast to the difficulty of
hydroboration previously encountered with the allene bearing a
free adjacent alcohol,[15,25] direct hydroboration of (R)-10 with
disiamylborane (Sia2BH) (11B: 53.7 ppm)[16] and subsequent
allylation of aldehyde 22 delivered anti,anti-diol 23 in 98% yield as
a single isomer (Scheme 4). This traceless protection strategy for
hydroboration of allenic alcohol circumvented the silyl protection
as shown in our previous study (ds 15/1).[12] Ketalization of the
diol in the presence of CSA followed by desilylation using TBAF
delivered compound 24 in quantitative yield. The following
oxidation, Henry reaction, and elimination were conducted in one-
pot to afford nitroalkene 25 in excellent yield. Although the oxa-
Michael cyclization was well precedented,[26] applications of this
reaction to nitro alkenes remains rare.[27] It is particularly
noteworthy that, upon treatment of para-methylbenzenesulfonic
acid (PTSA) to compound 25 in refluxing methanol, a tandem
process including deketalization, oxa-Michael addition, Nef
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aldehyde 30 to install the C17/C18 alkene while the
benzothiazolyl (BT) sulfone remained intact. The corresponding
sulfone 31 was then achieved in 83% isolated yield with an
excellent stereoselectivity (Z/E > 20/1).
pair of enantiomers, which were readily derived from the
decagram scale kinetic resolution of racemic α-allenic alcohol (15
longest linear steps from readily available rac-10, 12% overall
yield). The unprecedented iterative hydroboration/oxidation
converted the allene into the stereotriad of the B-ring. A cascade
process to construct the A-ring was superb and offers a platform
for derivatization. Moreover, for the first time, metastable borinate
and borane-ate complex were designed as traceless protection to
facilitate the crucial stereoselective hydroboration of allene and
alkene, debenzylation, and Julia olefination, which save additional
protection and deprotection operations. It is also noteworthy that
the reactivity-oriented design of bissulfone provided a C3-
homologation linker to react with two distinct aldehydes through a
sequential manner. The overall synthesis sequence also
circumvents additional transition metal removal steps.[35] By
implementing our previous tactics for the construction of
tetrahydropyran stereoisomers,[12] more macrolide analogs can
be assembled for future medicinal development.
A direct application of the free dienyl acid 21 (Scheme 5) to
Julia reaction was unsuccessful, suggesting protection of the acid
group to be necessary. Primary mechanistic studies revealed that
the complexation of the acid 21 with 9-BBN was complete after
30 min at 50 oC and two new signals (21a and 21b) were shown
in the 11B NMR spectra (32.8 and 19.7 ppm).[16,32] The ate-
complex was stable enough at room temperature and no
appreciable reduction of aldehyde was observed (Figure S7). To
this borane ate-complex solution, sulfone 31 and LiHMDS were
o
added at -75 C for the requisite Julia olefination. After acidic
work-up, the E-isomer of seco acid 32 was isolated in 65% yield.[33]
Finally, Yamaguchi macrolactonization[34] and subsequent global
desilylation were adopted to deliver the target molecule, (-)-
lasonolide A (4) (58% yield, 35.8 mg). The spectroscopic data of
the synthetic sample were identical to the original data [7] as well
as those reported in other synthetic studies.[9]
Acknowledgments
Financial support from the MOST Innovative Drug Discovery
(2018ZX09711001-005), the Shanghai Science and Technology
Commission (15JC1400400), the National Natural Science
Foundation of China (21472223), and the Chinese Academy of
Sciences (QYZDY-SSWSLH026 and XDB20020100) is highly
appreciated. We thank Jie Sun (SIOC) for the X-ray analysis and
Wenhua Li (SIOC) for assistance with the biotransformation.
Keywords: borane • hydroboration • macrolactonization •
olefination • oxa-Michael
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Entry for the Table of Contents (Please choose one layout)
Total Synthesis
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Lin Yang, Zuming Lin, Shunjie Shao,
Qian Zhao, and Ran Hong*
Page No. – Page No.
Enantioconvergent and Concise
Synthesis of Lasonolide A
The “gifted” borane! Stemming from classical hydroboration chemistry, a novel
traceless protection strategy for alcohol was designed and implemented in a concise
and modular synthesis of potent antitumor marine polyketide lasonolide A. The given
strategy paves a way to readily access derivatives for future medicinal investigation.
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