Synthesis and Structural Reassignment of Plakinidone

Article abstract of DOI:10.1021/acs.orglett.5b02599

In connection with its first synthesis, plakinidone was structurally revised to a five-membered lactone. The key evidence for the previous assignment of this natural product as a perlactone was proven to be a misinterpretation of the MS data because of unawareness of a facile air oxidation. The synthetic samples also allowed for detection of differences in ¹³C NMR for diastereomers of remote stereogenic centers, along with the influence of the air oxidation on the optical rotation.

Full text of DOI:10.1021/acs.orglett.5b02599

Letter
pubs.acs.org/OrgLett
Synthesis and Structural Reassignment of Plakinidone
Ze-Jun Xu, Dong-Xing Tan, and Yikang Wu*
State Key Laboratory of Bioorganic and Natural Product Chemistry, Collective Innovative Center for Chemistry and Life Sciences,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: In connection with its first synthesis, plakinidone
was structurally revised to a five-membered lactone. The key
evidence for the previous assignment of this natural product as a
perlactone was proven to be a misinterpretation of the MS data
because of unawareness of a facile air oxidation. The synthetic
samples also allowed for detection of differences in 13C NMR for
diastereomers of remote stereogenic centers, along with the
influence of the air oxidation on the optical rotation.
he marine sponges of the genus Plakortis are a rich source of
seemed that a model compound with a simple alkyl at the C17
would show NMR and optical rotation close to those for natural
1. Therefore, to access the core structure as quickly as possible we
began with a synthesis of perlactone 11.
T
cyclic peroxides.1 To date, nearly 100 such peroxides have
been isolated from various species of Plakortis. Essentially all of
the cyclic peroxides generated by Plakortis are either five- or six-
membered, with an ethereal link on both oxygen atoms of the
peroxy bonds, constituting a major family of cyclic organic
peroxides. This, along with the various bioactivities (including
antitumor and antiparasitic activities) already shown in a number
of cases, promoted the appearance of many elegant synthetic
approaches that are applicable to most (if not all) of the known
structural patterns of the peroxy functionalities in this family.2
During our study of organic peroxides, plakinidone3a (1,
Figure 1), an exception to all other cyclic peroxides from
As shown in Scheme 1, commercially available 3 was treated
with Eschenmoser’s6 salt to furnish known7 4, which was further
transformed into 6 using Evans’ asymmetric aldol condensation.
The chiral auxiliary was then removed with NaOMe. The
8
resulting ester 7 was treated with O2/Et3SiH/Co(acac)2 to
install the peroxy functionality (disappointedly, with poor
Scheme 1
Figure 1. Structure originally proposed for plakinidone (1) and
ircinianin (2), the reference compound for the assignment of a six-
membered perlactone ring in plakinidone (cf. ref 3a).
Plakoritis, caught our attention. As mentioned3 in the original
report, this was the first natural six-membered perlactone ever
identified. In fact, only two other natural perlactones (both being
eight-membered ones) can be found in the literature to date,4
one of which4b was later proven4c to be erroneously assigned.
These factors indicated that natural perlactones are extremely
rare; confirmation of the previously assigned structure for 1,
establishment of its absolute configuration, and development of
an entry to a structural motif of the plakortis peroxides not
covered yet by the existing syntheses2 thus appeared warranted.
Because the perlactone moiety in 1 is five CH2 units away from
the C11 stereogenic center5 and the remainder of the molecule, it
Received: September 9, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02599
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Organic Letters
Letter
stereoselectivity). Desilylation and lactonization led to 10 as
expected. However, subsequent oxidation of the C18 hydroxyl
group to afford 11 affected many broadly employed oxidation
protocols including Swern,9 Dess−Martin,10 IBX/DMSO,11
TPAP/NMO,12 PCC/NaOAc,13 TEMPO/NaOCl/KBr,14
TEMPO/PhI(OAc)2,15 TEMPO/Oxone,16 TEMPO/m-
CPBA,17 and AZADO/PhI(OAc)2.18 In most cases, the starting
10 was fully consumed, leading to rather polar/unidentifiable
products. Only when TEMPO/PhI(OAc)2 was used as the
oxidant did we manage to identify two of the minor products 12
and 13. The desired 11 was never detected.
led to the desired 21 in 65% yield, along with 24% of 22 (an
unprecedented case of carbine insertion into linear ketone alkyl
group20b). When DAMP/t-BuOK21 ws used as the reagent, the
yield for 21 was raised to 82% (without any 22 formed).
Oxidation under the CrO3/PCC/DMP22 conditions afforded
lactone 23 smoothly. Cleavage of the trityl group in 23 followed
by treatment with CBr4/Ph3P gave the desired bromide 24.
The C1−C12 fragment was synthesized as shown in Scheme 4.
Conversion23 of citronellal 25 into aldehyde 26 and subsequent
Scheme 4
The repeated failures prompted us to suspect whether the
assignment of 1 was incorrect. Upon closer inspection, we found
the MS and NMR evidence for the structure of 1 to be
unconvincing; in particular, the NMR discrepancies between 1
and 2 (ircinianin3b) did not necessarily disprove a five-membered
lactone moiety. Therefore, we next turned our attention to 16.
As shown in Scheme 2, lactonization of 9 led to 14. Although
subsequent oxidation under typical Swern conditions gave 15,
the desired 16 was eventually obtained using (CF3CO)2O
instead of (COCl)2.
Scheme 2
Lactone 16 indeed showed 1H and 13C NMR reasonably close
to those for the corresponding moieties in natural 1. Therefore,
we next decided to aim at a modified target structure, which has a
five-membered lactone instead of the perlactone.
The lactone fragment of the modified target was then
synthesized as shown in Scheme 3. Alkylation of the known19
17 with 18 gave 19, which on treatment with O3 and Ph3P
afforded 20. Subsequent treatment with Me3SiCHN2/n-BuLi20a
Wittig reaction with 27 furnished 28 as a 1.3:2 mixture of (Z)-
and (E)-isomers. Saturation of the C−C double bond with
diimide24 followed by hydrolysis of the acetal and the Wittig
condensation afforded alkene 29.
Scheme 3
A Suzuki coupling25 of 24 and 29 was then performed to afford
30 (Scheme 4). Subsequent oxidation with RuCl3/NaIO425 led
to diol 31 (56%) and ketone−alcohol 32 (25%). The diol could
be further oxidized to 32 with SO3·Py/DMSO/Et3N. The
redundant hydroxyl group was then removed by reduction26 with
SmI2. Finally, hydrogenolysis of the benzyl protecting group over
Pd/C afforded the end product 34.
Isolation and characterization of 34 were unexpectedly
difficult; the yield varied erratically from run to run, with
annoying additional signals “persisting” in the 1H and 13C NMR
spectra despite repeated chromatography. TLC monitoring
revealed that some minor species formed from 34 at ambient
temperature within ca. 1 h if no precautions were taken to
exclude air.
B
DOI: 10.1021/acs.orglett.5b02599
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Letter
Treatment of 34 containing those readily formed impurities
with Ph3P allowed for isolation of 36 (also attainable by
debenzylation of 32, Scheme 5). This, along with the δ 80.6 and
substantially oxidized28 and thus attempted to establish the
configurations for natural plakinidone through the [α]D for the
partially oxidized samples.29
The [α]D for 34 and epi-34 was then measured at ca. 10 h after
the first measurement of each sample, respectively, without any
precautions to exclude air (to mimic the apparent optical rotation
of the natural sample under the influence of the previously
unnoticed air oxidation, cf. Supporting Information). Two
diastereomers indeed behaved differently; 34 gave an apparent
[α]D of −2.84 (too small in magnitude), whereas epi-34 showed a
value of −9.3 (rather close in magnitude to 7.9), suggesting that
natural plakinidone is more likely to have the same relative
configuration as epi-34, although the absolute configuration is
opposite according to the sign for [α]D.
Scheme 5
The C11 racemic 34 showed two sets of resolved signals in
CDCl3 but (but not in CD3OD) at 36.5/36.4 ppm and 26.75/
26.78 ppm, respectively (cf. Supporting Information, Table S-6),
revealing an unexpected mutual differentiation between two
remote stereogenic centers.30 Because the resolved lines matched
the corresponding signals from 34 and epi-34, respectively, this
interesting phenomenon might be exploitable in determination
of the absolute configuration of natural plakinidone when a
natural sample is available.
In summary, the first synthesis of plakinidone was achieved. En
route to the synthesis, a so far unrecognized facile air oxidation
was identified that not only revealed the previous mis-
interpretation of the MS signal but also helped detect the errors
in the NMR and optical rotation data.31 With the aid of the
synthetic samples, the structure of natural plakinidone was
reliably revised, while the absolute configuration was tentatively
assigned as (11S,17S) on the basis of the estimation of oxidation-
associated changes in the optical activity.32 The mutual
differentiation in 13C NMR between two remote stereogenic
centers observed here may also be exploitable in configuration
assignments of similar alkyl-only centers (rather difficult due to
lack of heteroatoms/functional groups in vicinity). Finally, the
unique (to our knowledge) carbine insertion into the linear
ketone alkyl group, the outcome of using (CF3CO)2O in
oxidation of 14 instead of (COCl)2, and the phenol-accelerated
air oxidation of five-membered enol lactones27 also deserve
particular attention.
80.1 ppm signals for the C19 in 13C NMR for the crude mixture
(cf. the 69.8 and 69.3 ppm in 36), revealed a facile27 air oxidation
of 34 leading to 35 (unstable, tending to decompose to give 36).
Spontaneous generation of 36 also occurred during EI-HRMS
analysis: even pure 34 (C23H34O4) still showed a distinct signal at
m/z = 390.2408 (C23H34O5); the critical piece of evidence for the
assignment of plakinidone as a perlactone in the previous3 study
was thus proven to be a misunderstanding.
Exclusion of air from the NMR solvent effectively reduced the
extra signals in 13C NMR of 34, giving a rectified spectrum that
agreed very well with that for natural plakinidone (cf. Table S-1,
Supporting Information). It was thus concluded that natural
plakinidone and 34 must have the same planar structure.
Determination of configurations for plakinidone was un-
expectedly difficult. In principle, either 34 or epi-34 (Figure 2)
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02599.
Experimental procedures, spectroscopic data listing/
scanned spectra for products (new compounds), 13C
NMR data comparison tables, and time/concentration-
dependent optical rotation data for 34 (PDF)
Figure 2. Diastereomers of 34 and their [α]D measured at c = 0.61 in
MeOH. For the synthesis of epi-34 and C-11 racemic 34 (which showed
the contribution of each stereogenic center to the observed optical
rotation); see the Supporting Information.
AUTHOR INFORMATION
Corresponding Author
■
should possess the same relative configuration as plakinidone and
thus must have the same magnitude for the [α]D. However, the
specific rotation for 34 (practically free from 36) was determined
to be +1.20 (c 0.61, MeOH), while the corresponding data for
epi-34 were −4.40 (c 0.61, MeOH); neither was compatible with
the [α]D +7.9 for natural plakinidone and thus made the
configuration assignment a “mission impossible”.
Then, enlightened by the newly identified air oxidation of 34
and the IR data for the natural sample (1800 and 1760 cm−1,
Scheme 5), we envisaged that the natural sample might be
*E-mail: yikangwu@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (215732002, 21372248, 21172247) and
the Chinese Academy of Sciences.
C
DOI: 10.1021/acs.orglett.5b02599
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Letter
see: Liu, H.; Sun, C.; Lee, N.-K.; Henry, R. F.; Lee, D. Chem. - Eur. J.
2012, 18, 11889−11893.
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