Plakortolide stereochemistry revisited: The checkered history of plakortolides e and i

Article abstract of DOI:10.1021/np3005634

The relative configuration of the plakortolide metabolite (4) isolated from a Madagascan Plakortis sp. and named (+)-plakortolide I is revised following reassignment of the ¹³C signals for C-7 and C-16, thereby establishing that the metabolite isolated was likely (+)-plakortolide E (3). We propose that the name plakortolide I should be retained for the plakortolide metabolite 5 first isolated by the Faulkner group; its enantiomer 4 can then be named ent-plakortolide I in line with the description of Barnych and Vatèle. The spectroscopic data for MPA esters prepared from synthetic samples of seco derivatives of plakortolide E (3) and ent-plakortolide I (4) were compared with those of MPA esters of seco derivatives from naturally isolated plakortolides L (1) and K (2) and of seco-plakortolide E (6a). Likewise, the spectroscopic data for MTPA esters derived from 3 and 4 were compared with data for the MTPA esters derived from 5. These various comparisons established that the sign of the specific rotation associated with the natural isolates is an unreliable indicator of absolute configuration and verify that the absolute configurations of plakortolides L (1), K (2), E (3), and I (5) are (3S, 4S, 6S), (3R, 4R, 6S), (3R, 4R, 6R), and (3S, 4S, 6R), respectively.

Full text of DOI:10.1021/np3005634

Article
pubs.acs.org/jnp
Plakortolide Stereochemistry Revisited: The Checkered History of
Plakortolides E and I
Ken W. L. Yong,† Bogdan Barnych,‡ James J. De Voss,† Jean-Michel Vatele,*,‡ and Mary J. Garson*,†
̀
†School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane QLD 4072, Australia
‡Institut de Chimie et Biochimie Molec
SURCOOF, Bat
́
ulaires et Supramolec
iment Raulin, 43 Boulevard du 11 Novembre 1918, Villeurbanne Cedex, France
́
ulaires (ICMBS), Universite
́
Lyon 1, UMR 5246 CNRS, Equipe
́
̂
S
* Supporting Information
ABSTRACT: The relative configuration of the plakortolide metabolite
(4) isolated from a Madagascan Plakortis sp. and named (+)-plakortolide I
is revised following reassignment of the 13C signals for C-7 and C-16,
thereby establishing that the metabolite isolated was likely (+)-plakorto-
lide E (3). We propose that the name “plakortolide I” should be retained
for the plakortolide metabolite 5 first isolated by the Faulkner group; its
enantiomer 4 can then be named ent-plakortolide I in line with the
description of Barnych and Vatele. The spectroscopic data for MPA esters
̀
prepared from synthetic samples of seco derivatives of plakortolide E (3)
and ent-plakortolide I (4) were compared with those of MPA esters of seco
derivatives from naturally isolated plakortolides L (1) and K (2) and of
seco-plakortolide E (6a). Likewise, the spectroscopic data for MTPA esters
derived from 3 and 4 were compared with data for the MTPA esters
derived from 5. These various comparisons established that the sign of the specific rotation associated with the natural isolates is
an unreliable indicator of absolute configuration and verify that the absolute configurations of plakortolides L (1), K (2), E (3),
and I (5) are (3S, 4S, 6S), (3R, 4R, 6S), (3R, 4R, 6R), and (3S, 4S, 6R), respectively.
reported from the Fijian sponge Plakortis sp., has a
Ph(CH2)10− side chain and is a homologue of plakortolide L
(1). Plakortolide I (4), also with a Ph(CH2)10− side chain, was
obtained from the Madagascan Plakortis aff. simplex by
Kashman and co-workers and was characterized by them as
the enantiomer of an unnamed plakortolide metabolite (5)
isolated earlier by the Faulkner research group from a
Philippines Plakinastrella sp.6 The published structures of
metabolites 4 and 5 are homologues of plakortolide K (2)
(Figure 1).
In this report, we clarify issues of relative configuration for
plakortolide metabolites and thereby establish that the
Kashman group likely isolated plakortolide E (3) rather than
plakortolide I (4). We also detail the unreliability of specific
rotation measurements in the determination of absolute
configuration within the plakortolide class of metabolites.
ur detailed study of the Australian marine sponge
OPlakinastrella clathrata Kirkpatrick, 1900 has revealed
that this sponge is a rich source of plakortolide metabolites
possessing a Ph(CH2)12− side chain, their peroxy ring-opened
(seco) derivatives, and stereochemically related plakortone
ethers.1 In addition, the sponge extract contained Ph(CH2)10−
or alkyl side chain functionalized plakortolides, together with
some diperoxides (that may derive from side chain oxidation of
plakortolides) and various side-chain-truncated plakortolides.2
The study on P. clathrata further addressed issues of relative
and absolute configuration, in particular revealing that
diastereomeric plakortolides, such as plakortolides L (1) and
K (2), uniformly had a 6S configuration and thus differed in
configuration at the biosynthetically linked C-3 and C-4
centers. This stereochemical situation led to a proposal that
the plakortolide biosynthetic pathway in P. clathrata involves
cyclization of 6-hydroperoxydienoic acid intermediates arising
from the stereospecific attachment of a C-6 hydroperoxy group
onto a polyketide-derived precursor.1
Recently we described an enantiospecific synthesis of the
diastereomeric plakortolides E (3)3 and I (4)4 that involved a
synthetic route modeling the above proposed plakortolide
biosynthetic pathway. The peroxylactone core of the
plakortolides was efficiently constructed from (S)-2-methyl-
glycidol by diastereoselective Mukaiyama aldol reaction,
regioselective hydroperoxidation, and intramolecular hetero-
Michael addition onto a butenolide.5 Plakortolide E (3), first
RESULTS AND DISCUSSION
■
1
Relative Configurational Issues. Analysis of the H and
13C NMR values for C-7 and the C-6 methyl substituent of
plakortolides, together with relevant NOE data,1,5 guides the
correct determination of their relative configuration. Typical
data for plakortolide L (1) compared to those of its
diastereomer plakortolide K (2) are as follows: 1, C-7 δC
Received: August 19, 2012
Published: October 15, 2012
© 2012 American Chemical Society and
American Society of Pharmacognosy
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Journal of Natural Products
Article
Figure 1. Selected plakortolide metabolites with a Ph(CH2)12− or Ph(CH2)10− side chain.
1
Table 1. Comparison of H and 13C NMR Assignments for Synthetic and Natural Samples of Plakortolides E and I
a
b
synthetic plakortolide E (3)
natural plakortolide E (3)
synthetic plakortolide I (4)
natural plakortolide I (5)
c
d
e
f
c
d
g
h
position
δC
174.2
δH (J in Hz)
δC
δH (J in Hz)
δC
174.1
δH (J in Hz)
δC
174.1
δH (J in Hz)
1
174.2
34.2
2a
2b
3
34.3
2.92, dd (18.5, 6.1)
2.62, d (18.5)
2.91, dd (12.4, 6.0)
2.70, d (12.4)
34.1
2.90, dd (18.5, 5.9)
2.56, d (18.5)
34.1
2.91, dd (18.6, 6.0)
2.59, dd (18.6, 1.5)
4.49, d (6.0)
81.1
82.8
40.6
4.45, d (6.1)
80.1
82.0
39.5
4.44, d (6.0)
80.8
82.5
40.2
4.48, d (5.9)
80.8
82.5
40.2
4
i
5a
5b
6
2.17, d (14.8)
1.71, d (14.8)
2.17, d (15.0)
1.71, d (15.0)
2.27, d (15.0)
1.65, d (15.0)
2.28, d (15.3)
1.66, d (15.3)
80.1
41.0
23.1
80.2
41.0
80.2
36.9
80.2
36.9
23.7
i
i
7
1.50, m
1.50, m
1.52−1.76, m
1.26, m
1.75, m
8
1.27, m
23.0
1.25, m
23.7
1.27−1.30, m
1.27−1.30, m
1.57, m
9−14
15
16
17
18
19
20
21
22
29.3−30.0
31.5
1.27, m
29.5
1.25, m
29.3−29.9
31.5
1.26, m
29.3−29.9
31.5
1.61, m
31.4
1.58, m
1.61, m
i
36.0
2.60 (t, 7.7)
36.0
2.60 (t, 7.0)
36.0
2.60 (t, 7.8)
36.0
2.60 (t, 7.8)
142.9
128.4
128.2
125.5
25.9
142.2
128.3
128.2
125.5
25.8
143.0
128.4
128.2
125.5
25.9
143.0
128.4
128.2
125.5
25.9
7.15−7.29 (m)
7.15−7.29 (m)
7.15−7.29 (m)
1.39, s
7.20−7.25 (m)
7.20−7.25 (m)
7.20−7.25 (m)
1.37, s
7.15−7.29 (m)
7.15−7.29 (m)
7.15−7.29 (m)
1.37, s
7.19, m
7.27, m
7.19, m
1.38, s
1.20, s
i
22.4
1.29, s
22.4
1.27, s
24.8
1.20, s
24.9
a
b
c
Data from ref 4; revised structure (see text); sample originally named as plakortolide I. Data from ref 6. 100 MHz; chemical shifts (ppm)
d
e
referenced to CDCl3 (δC 77.16). 400 MHz; chemical shifts (ppm) referenced to CHCl3 (δH 7.26). 100 MHz; chemical shifts (ppm) referenced to
CDCl3 (δC 77.0). 500 MHz; chemical shifts (ppm) referenced to TMS. 100 MHz; reference not stated. 300 MHz; reference not stated. Revised
f
g
h
i
assignments (see text for details).
40.8; C-24, δH 1.27; δC 22.2 vs 2, C-7 δC 36.6; C-24, δH 1.18; δC
24.4. Additionally, the diastereotopic H-5 signals are diagnostic:
for 1, δH 2.15 and 1.68 vs 2, δH 2.25 and 1.63.1 Against this
background, when the literature data4 for the structure 4 named
as “plakortolide I” were examined, some inconsistencies became
apparent. In the 1H NMR data, the chemical shift values of the
C-5 protons (δH 2.17 and 1.71) and of Me-22 (δH 1.27) were
all more consistent with a trans arrangement of the C-4 and C-6
Me groups than with the published cis arrangement. On first
inspection, the 13C NMR data appeared to match the proposed
structure (C-7 δC 36.0), but on closer inspection, the published
value (δC 39.5) for the benzylic C-16 appeared incorrect. The
chemical shift value for this carbon is generally ∼36.0 ppm.1
The NMR assignments of synthetic samples of diastereomers 3
and 4 were examined by HSQC analysis, and the following
assignments were confirmed: 3, δC 40.6 (C-5); δC 41.0 (C-7);
δC 36.0 (C-16); δC 22.4 (Me-22); and 4, δC 40.2 (C-5); δC 36.9
(C-7); δC 36.0 (C-16); δC 24.8 (Me-22). Against this
background, we reviewed the assignments for the “plakortolide
I” sample isolated by the Kashman group and suggest that the
signals originally assigned to C-5 (δC 41.0), C-7 (δC 36.0), and
C-16 (δC 39.5) should be revised to C-5 (δC 39.5), C-7 (δC
41.0), and C-16 (δC 36.0). Furthermore, we suggest that the
chemical shift values originally assigned to C-8 (δC 22.4) and
Me-22 (δC 23.0) should be revised to C-8 (δC 23.0) and Me-22
(δC 22.4) so that the assignment for Me-22 is consistent with
typical values for a plakortolide structure.1 With these proposed
1
changes, as shown in Table 1, the H and 13C NMR data
reported by Kashman and co-workers4 matched well those of
synthetic plakortolide E5 except for the geminal coupling
constant reported for H-2 and for small discrepancies (<1
ppm) in the values for C-3, C-4, and C-5.7 The revised 13C
NMR assignments now also implied that the C-4Me/C-6Me
groups in “plakortolide I” are in a trans rather than a cis
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Table 2. Revised Structures and Names of Selected Plakortolide Metabolites
original structure
published configuration
new structure or name
revised configuration
comments
plakortolide E (3)
3R, 4R, 6R
3R, 4R, 6S
3S, 4S, 6R
seco-plakortolide E (6a)
plakortolide E (3)
plakortolide I (5)
unchanged
3R, 4R, 6R
unchanged
plakortolide I (4)
structure 4 named as
ent-plakortolide I
unnamed plakortolide (5)
Table 3. Comparison of MPA and MTPA Ester Data for Synthetic seco-Plakortolide E and the seco Derivative of ent-Plakortolide
I with Those of Equivalent Esters Prepared from seco Derivatives of Natural Plakortolides E, I, K, and L
seco-plakortolide E
(synthetic) (6a)5
ent-seco-plakortolide I
(synthetic) (7a)
seco-plakortolide K
(8a)1
seco-plakortolide L
(9a)1
seco-plakortolide E
seco-plakortolide I
a
(6a)3
11a6
,
ΔδRS
MPA
6b
ΔδSR
MTPA
6c
ΔδRS
MPA
7b
ΔδSR
MTPA
7c
ΔδRS MPA
ΔδRS MPA
ΔδRS MPA
ΔδSRMTPA
position
8b
9b
10
11b
H2
0.09
0.23
0.02
0.08
0.09
0.25
0.02
0.08
0.09
0.25
−0.08
−0.22
0.05
0.10
−0.023
−0.0005
0.026
H2′
C-4 Me
0.10
b
−0.06
−0.34
−0.37
−0.31
−0.03
−0.14
−0.08
−0.17
−0.04
−0.33
−0.39
−0.16
−0.02
−0.12
−0.10
−0.07
−0.04
−0.33
−0.39
−0.16
b
b
b
H5
0.36
0.122
H5′
C-6 Me
0.33
0.106
0.29
0.061
a
b
MPA ester of a TBDPS-protected tetraol prepared from the natural product by LiAlH4 reduction. Chemical shift data not provided in ref 3.
arrangement. Consequently, the structure of the Kashman
isolate most likely corresponds to that of plakortolide E (3).
The erroneous stereochemical determination published by
the Kashman group may have been compromised since the
spectroscopic data originally attributed to plakortolide E (3)
did not match the structure proposed.3 In our own structural
work, a comparison of NMR data for synthetic seco diols
prepared by Zn/AcOH reduction of plakortolides K (2) and L
(1) with relevant literature data led us to conclude that the
NMR data published for plakortolide E (3) were in fact those
of the seco diol (6a).1 The subsequent synthesis of both
plakortolide E (3) and seco-plakortolide E (6a) further
confirmed that incorrect chemical shift data had originally
been provided for plakortolide E (3).5
Clarification of Absolute Configuration of Plakorto-
lides. Synthetic samples of plakortolide E (3), with a
(3R,4R,6R) configuration, and ent-plakortolide I (4), with a
(3R,4R,6S) configuration, have [α]D values of +14.9 (c 0.76,
CHCl3) and −9 (c 0.7, CHCl3), respectively.5 Synthetic
samples of seco-plakortolide E (6a), of (3R,4R,6R) config-
uration,3 and the ent isomer of seco-plakortolide I (7a), of
(3R,4R,6S) configuration, have [α]D values of +6.9 (c 0.15,
CHCl3)9 and +9.8 (c 0.27, CHCl3), respectively
When compared to these reference values, the specific
rotation values published for some plakortolide metabolites
appear inconsistent. Plakortolide I (5), with a reported [α]D −8
(c 0.05, CHCl3), was deduced to have a 3S configuration from
MPA ester analysis.6 However, since the synthetic sample of
ent-plakortolide I (4), with a 3R configuration, has a negative
rotation, the specific rotation for 5 should have been positive.
Plakortolide K (2), with a reported [α]D +8.8 (c 0.03, CHCl3),
was deduced to have a 3R configuration from MPA ester
analysis.1 However, in view of the sign of rotation of ent-
plakortolide I (4), a negative rotation would have been
expected for 2. It is generally accepted that chiral homologues
should possess the same sign of optical rotation, although there
are exceptions to this rule.10 Noting that the various
measurements were made at different concentrations and on
different instruments, the optical rotation of synthetic 4 was
recorded at a lower concentration, giving an averaged [α]D −11
(c 0.04, CHCl3), and with a range of specific rotations that
varied between −13 and −8. For comparison, the individual
[α]D values for the plakortolide K (2) sample ranged between
A clarification in nomenclature is required. Owing to the
apparent correction of absolute configuration for “plakortolide
I” in the synthetic study,5 stereoisomer 4 was named ent-
plakortolide I rather than plakortolide I. The enantiomer 5,
previously unnamed, can therefore be named plakortolide I.
This is preferable to the previous name of 6-epiplakortolide E
given to 5 by Jung et al. in a paper describing the synthesis of
racemic 5,8 because the latter name is misleading. Both 33 and
56 have been shown by Mosher ester analysis to possess a 6R
configuration, and so these two metabolites cannot be C-6
1
epimers. For reference, the H and 13C NMR data of synthetic
ent-plakortolide I (4) and of natural plakortolide I (5) are
shown in Table 1 alongside the data of natural and synthetic
plakortolide E (3). Table 2 summarizes the changes in
nomenclature that we recommend.
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+20 and −1, resulting in the averaged value of +8.8 that was
reported. A further sample of plakortolide K (2) was next
isolated from sponge crude extract and gave [α]D values from
−8 to −14 (c 0.04, CHCl3), leading to an averaged value of
−11, which agreed with that of the synthetic sample of the
homologue ent-plakortolide I. The specific rotation data for the
seco derivatives of 2 and 4 were also compared. seco-
Plakortolide K (8a) prepared from natural material had [α]D
+13.5 (c 0.04, CHCl3) and with the range of individual
measurements between +11 and +16, compared to +9.8 (c 0.27,
CHCl3) for the seco derivative of synthetic ent-plakortolide I
(7a). There was also better agreement when data for
plakortolide L (1) were compared with those of plakortolide
E (3). Plakortolide L (1), with an [α]D −4.6 (c 0.16, CHCl3)
averaged across individual values that ranged from −9.6 to −1.5
and a 3S configuration from MPA ester analysis,1 had the
opposite sign of rotation compared to synthetic 3, of 3R
configuration. seco-Plakortolide L (9a) prepared from natural
material had [α]D −11.0 (c 0.04, CHCl3) compared to +6.9 (c
0.15, CHCl3)9 for the seco derivative (6a) of synthetic
plakortolide E.
natural products that involve a comparison with the data for
candidate synthetic stereoisomers can easily be compromised
by the experimental and instrumental errors inherent in optical
rotation measurements, by variations in temperature, solvent,
or concentration,12 or by the presence of chiral impurities,13
each of which may impact on small rotation values. Rigid
molecules, for example 5-substituted-2(5H)-furanones of the
same absolute configuration, have been shown to exhibit
specific rotations of opposite sign.10 In the case of conforma-
tionally flexible molecules, the equilibrium population of the
various conformers generates a conformationally averaged [α]D
value.14 For example, the marine alkaloids haliclonacyclamines
A and B, with small [α]D values that are opposite in sign, were
assigned the same absolute configuration by X-ray crystallog-
raphy using Cu Kα radiation. These two alkaloids differed in
conformation solely as a consequence of different double-bond
positioning in the methylene chains connected to the
bipiperidine core.15 Low-temperature NMR studies (to be
reported in detail elsewhere) have confirmed the conforma-
tional flexibility of the peroxylactone moiety in plakortolides.
Although, understandably, the experimental error associated
with the measurement of dilute samples is significant, we
wished to be sure that this was the source of the error. An
alternative explanation for the inconsistencies was that the
various MPA or MTPA analyses were somehow misleading.11
MPA esters 6b and 7b were therefore prepared from synthetic
samples of seco-plakortolide E (6a) and the seco derivative of
ent-plakortolide I (7a), respectively, and their NMR data
compared with those of the equivalent esters1,3 prepared from
natural plakortolides (Table 3). First, comparison of the MPA
esters 9b obtained from seco-plakortolide L (9a)1 with MPA
esters 6b confirmed that natural (−)-plakortolide L (1) and
synthetic (+)-plakortolide E (3) have opposite configurations
(1 3S, 4S, 6S; 3 3R, 4R, 6R). Analysis of the MPA esters (10)
prepared earlier from a derivative of (+)-seco-plakortolide E by
Varoglu et al. had also yielded a 3R configuration, although it
should be noted that their report contained limited NMR data.3
These various experiments all support a consistency between
optical rotation data and Mosher ester results in plakortolides
with a trans arrangement of the C-4 and C-6 methyl groups. On
the basis of the reported specific rotation of +8 (c 0.0173,
CHCl3),4 and subject to the caveat explored above, it seems
likely that the Kashman group may have isolated (3R,4R,6R)-
plakortolide E (3) from Plakortis aff. simplex.
CONCLUSIONS
■
The structure of a plakortolide metabolite isolated from
Plakortis aff. simplex and named “plakortolide I” is revised to
that of plakortolide E, likely of (3R,4R,6R) configuration. We
suggest that the plakortolide I name can be retained for the
stereoisomeric metabolite 5 isolated earlier by the Faulkner
group from a Philippino Plakinastrella sp. Specific rotation data
should be used with caution to determine the absolute
configuration of plakortolides, notably in those cases where
there is a cis configuration for the C-4 and C-6 methyl groups.
Instead, analysis of NMR data for MPA or MTPA ester
derivatives leads to a reliable determination of the absolute
configuration. Such comparisons were used to verify that the
absolute configurations of plakortolides K (2) and I (5) are
(3R, 4R, 6S) and (3S, 4S, 6R), respectively, while those of
plakortolides L (1) and E (3) are (3S, 4S, 6S) and (3R, 4R, 6R),
respectively.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Optical rotations were
obtained using a JASCO P-2000 polarimeter (U. Qld) or a Perkin-
Elmer 343 polarimeter (U. Lyon) for solutions in CHCl3. NMR
spectra were recorded at ambient probe temperature on a Bruker AV
500 spectrometer unless otherwise stated. 1H NMR spectra were
referenced to the residual solvent peak at δ = 7.26 (CHCl3). 13C NMR
spectra were referenced to the solvent peak at δ = 77.16 (CDCl3).
HRMS analyses were conducted using a Thermofinigan MAT 95 XL
instrument. Reagents and solvents were purified by standard means.
DCM was distilled from CaH2. Analytical TLC was performed on
Merck silica gel 60 F254 plates. Flash chromatography was performed
on silica gel (230−400 mesh) purchased from Macherey Nagel. PTLC
was performed on Silicycle plates (F-254, 1000 μm).
In contrast, MPA esters 7b and 8b, prepared from synthetic
(−)-ent-plakortolide I (4)5 and natural plakortolide K (2),1
respectively, were each assigned a (3R, 4R, 6S) configuration,
despite the positive specific rotation originally reported for 2.
Furthermore, comparison of the NMR data for MTPA esters
(7c) of 4 with the literature data for MTPA esters (11) derived
from plakortolide I (5)6 revealed an enantiomeric relationship
(4 3R, 4R, 6S; 5 3S, 4S, 6R), despite both 4 and 5 showing a
negative specific rotation. These data clearly establish the
inadvisability of using specific rotation data measured at the
sodium D wavelength to establish absolute configuration in
plakortolides for which there is a cis arrangement of the C-4
and C-6 methyl groups.
Seco Derivative of ent-Plakortolide I (7a). To a solution of ent-
plakortolide I (4) (6.3 mg, 0.016 mmol) in anhydrous Et2O (2 mL)
were added HOAc (709 μL, 80 equiv) and Zn (42 mg, 4 equiv). The
mixture was stirred for 24 h, filtered, and evaporated to give the seco
derivative of ent-plakortolide I (7a) (6.2 mg, 98% yield): [α]20D +9.8 (c
1
0.27, CHCl3); H NMR (500 MHz, CDCl3) δH 7.29−7.26 (2H, m),
We have previously commented1 that “the small magnitude
of [α]D values associated with many of the plakortolide
metabolites isolated suggests that it would be speculative to
assign either absolute or relative configuration on the basis of
[α]D values alone.” Stereochemical determinations for complex
7.18−7.15 (3H, m), 4.24 (1H, d, J = 5.9 Hz), 2.91 (1H, dd, J = 18.1,
6.0 Hz), 2.60 (2H, t, J = 7.8 Hz), 2.53 (1H, d, J = 18.1 Hz), 2.38 (1H,
d, J = 14.7 Hz), 1.88 (1H, d, J = 14.7 Hz), 1.64−1.52 (4H, m), 1.47
(3H, s), 1.36 (3H, s), 1.27 (14H, m); 13C NMR (126 MHz, CDCl3)
δC 175.2, 143.1, 128.5, 128.4, 125.7, 90.6, 73.6, 72.9, 46.7, 44.2, 37.9,
1795
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36.1, 31.7, 30.0, 29.7 (3C), 29.6, 29.5, 28.5, 26.2, 24.1; HR-ESIMS m/z
413.2662 [M + Na]+ (calculated for C24H38NaO4 413.2650).
tate. The (S)-MPA derivative of ent-seco-plakortolide I (1 mg, 68%)
was obtained as a colorless oil: 1H NMR (500 MHz, CDCl3) δH 7.43−
7.34 (5H, m), 7.29−7.26 (2H, m), 7.18−7.15 (3H, m), 5.23 (1H, dd, J
= 6.3, 1.4 Hz), 4.80 (1H, s), 3.41 (3H, s), 2.96 (1H, dd, J = 18.5, 6.3
Hz), 2.60 (2H, t, J = 7.8 Hz), 2.24 (1H, dd, J = 18.5, 1.5 Hz), 1.84
(1H, d, J = 15.0 Hz), 1.80 (1H, d, J = 15.0 Hz), 1.56 (3H, s), 1.63−
1.24 (18H, m), 1.28 (3H, s); 13C NMR (126 MHz, CDCl3) δC 173.5,
169.8, 143.1, 135.5, 129.3, 129.0, 128.5, 128.4, 127.1, 125.7, 88.2, 82.7,
76.6, 72.4, 57.6, 45.9, 43.6, 36.1, 35.5, 31.7, 30.3, 29.80, 29.78, 29.73,
29.67, 29.5, 27.9, 25.0, 23.9; HR-ESIMS m/z 561.3165 [M + Na]+
(calculated for C33H46NaO6 561.3187).
(R)-(2R,3R)-2-[(S)-2-Hydroxy-2-methyl-12-phenyldodecyl]-2-
methyl-5-oxotetrahydrofuran-3-yl 3,3,3-Trifluoro-2-methoxy-
2-phenylpropanoate. The (R)-MTPA derivative of ent-seco-
plakortolide I (0.5 mg, 30%) was obtained as a colorless oil: 1H
NMR (500 MHz, CDCl3) δH 7.50−7.41 (5H, m), 7.29−7.26 (2H, m),
7.18−7.15 (3H, m), 5.31 (1H, dd, J = 6.2, 1.7 Hz), 3.46 (3H, m), 3.11
(1H, dd, J = 18.7, 6.2 Hz), 2.60 (2H, t, J = 7.8 Hz), 2.47 (1H, dd, J =
18.6, 1.7 Hz), 1.86 (1H, d, J = 15.1 Hz), 1.77 (1H, d, J = 15.1 Hz),
1.61 (3H, s), 1.62−1.20 (18H, m), 1.27 (3H, s); HR-ESIMS m/z
629.3045 [M + Na]+ (calculated for C34H45F3NaO6 629.3060).
(S)-(2R,3R)-2-[(S)-2-Hydroxy-2-methyl-12-phenyldodecyl]-2-
methyl-5-oxotetrahydrofuran-3-yl 3,3,3-Trifluoro-2-methoxy-
2-phenylpropanoate. The (S)-MTPA derivative of ent-seco-
plakortolide I (0.5 mg, 30%) was obtained as a colorless oil: 1H
NMR (500 MHz, CDCl3) δH 7.52−7.40 (5H, m), 7.30−7.26 (2H, m),
7.19−7.15 (3H, m), 5.30 (1H, dd, J = 6.1, 1.4 Hz), 3.56 (3H, m), 3.13
(1H, dd, J = 18.7, 6.1 Hz), 2.60 (2H, t, J = 7.8 Hz), 2.55 (1H, dd, J =
18.7, 1.4 Hz), 1.74 (1H, d, J = 15.0 Hz), 1.67 (1H, d, J = 15.1 Hz),
1.59 (3H, s), 1.64−1.21 (18H, m), 1.20 (3H, s); HR-ESIMS m/z
629.3038 [M + Na]+ (calculated for C34H45F3NaO6 629.3060).
Procedure for the Preparation of MPA or MTPA Esters. The
seco derivatives (6a, 7a) of plakortolide E (3)5 or ent-plakortolide I (4)
(1 mg, 2.56 μmol, 1 equiv) were individually treated with MPA (2.1
mg, 12.8 μmol, 5 equiv) or MTPA (3 mg, 12.8 μmol, 5 equiv)
followed by DCC (2.6 mg, 12.8 μmol, 5 equiv) and DMAP (1.6 mg,
12.8 μmol, 5 equiv) in dry DCM (0.6 mL). Each reaction was stirred
for 1−2 h, filtered through a small pad of silica gel, concentrated to 0.2
mL, and chromatographed on preparative TLC (Et2O).
(R)-(2R,3R)-2-[(R)-2-Hydroxy-2-methyl-12-phenyldodecyl]-2-
methyl-5-oxotetrahydrofuran-3-yl 2-Methoxy-2-phenylace-
tate. The (R)-MPA derivative of seco-plakortolide E (0.9 mg, 66%)
was obtained as a colorless oil: 1H NMR (500 MHz, CDCl3) δH 7.44−
7.35 (5H, m), 7.29−7.26 (2H, m), 7.19−7.16 (3H, m), 5.21 (1H, dd, J
= 6.0, 1.1 Hz), 4.76 (1H, s), 3.38 (3H, s), 3.05 (1H, dd, J = 18.6, 6.1
Hz), 2.60 (2H, t, J = 7.8 Hz), 2.50 (1H, dd, J = 18.5, 1.2 Hz), 1.59
(1H, d, J = 15.2 Hz), 1.66−1.53 (4H, m), 1.49 (3H, s), 1.41 (1H, d, J
= 15.2 Hz), 1.37−1.22 (14H, m), 0.84 (3H, s); 13C NMR (126 MHz,
CDCl3) δC 173.4, 169.5, 143.1, 135.6, 129.5, 129.2, 128.5, 128.4, 127.7,
125.7, 88.4, 82.4, 76.3, 72.1, 57.3, 43.4, 43.0, 36.1, 36.0, 31.7, 30.2,
29.80, 29.78, 29.74, 29.68, 29.5, 28.4, 24.8, 24.0; HR-ESIMS m/z
561.3172 [M + Na]+ (calculated for C33H46NaO6 561.3187).
(S)-(2R,3R)-2-[(R)-2-Hydroxy-2-methyl-12-phenyldodecyl]-2-
methyl-5-oxotetrahydrofuran-3-yl 2-Methoxy-2-phenylace-
tate. The (S)-MPA derivative of seco-plakortolide E (0.9 mg, 68%)
was obtained as a colorless oil: 1H NMR (500 MHz, CDCl3) δH 7.42−
7.35 (5H, m), 7.29−7.26 (2H, m), 7.18−7.16 (3H, m), 5.21 (1H, dd, J
= 6.3, 1.6 Hz), 4.81 (1H, s), 3.41 (3H, s), 2.96 (1H, dd, J = 18.5, 6.4
Hz), 2.60 (2H, t, J = 7.8 Hz), 2.27 (1H, dd, J = 18.6, 1.6 Hz), 1.93
(1H, d, J = 15.1 Hz), 1.78 (1H, d, J = 15.0 Hz), 1.64−1.47 (4H, m),
1.55 (3H, s), 1.37−1.24 (14H, m), 1.15 (3H, s); 13C NMR (126 MHz,
CDCl3) δC 173.2, 169.8, 143.1, 135.4, 129.3, 129.1, 128.5, 128.4, 127.0,
125.7, 88.1, 82.6, 76.4, 72.3, 57.6, 44.1, 43.4, 36.1, 35.6, 31.7, 30.2,
29.81, 29.77, 29.73, 29.67, 29.5, 28.8, 25.2, 24.3; HR-ESIMS m/z
561.3177 [M + Na]+ (calculated for C33H46NaO6 561.3187).
(R)-(2R,3R)-2-[(R)-2-Hydroxy-2-methyl-12-phenyldodecyl]-2-
methyl-5-oxotetrahydrofuran-3-yl 3,3,3-Trifluoro-2-methoxy-
2-phenylpropanoate. The (R)-MTPA derivative of seco-plakortolide
E (0.63 mg, 39%) was obtained as a colorless oil: 1H NMR (500 MHz,
CDCl3) δH 7.50−7.42 (5H, m), 7.29−7.26 (2H, m), 7.18−7.15 (3H,
m), 5.30 (1H, dd, J = 6.3, 2.1 Hz), 3.46 (3H, m), 3.10 (1H, dd, J =
18.6, 6.4 Hz), 2.60 (2H, t, J = 7.8 Hz), 2.49 (1H, dd, J = 18.6, 2.1 Hz),
1.95 (1H, d, J = 15.2 Hz), 1.75 (1H, d, J = 15.2 Hz), 1.60 (3H, s),
1.64−1.20 (18H, m), 1.14 (3H, s); HR-ESIMS m/z 629.3057 [M +
Na]+ (calculated for C34H45F3NaO6 629.3060).
(S)-(2R,3R)-2-[(R)-2-Hydroxy-2-methyl-12-phenyldodecyl]-2-
methyl-5-oxotetrahydrofuran-3-yl 3,3,3-Trifluoro-2-methoxy-
2-phenylpropanoate. The (S)-MTPA derivative of seco-plakortolide
E (0.68 mg, 42%) was obtained as a colorless oil: 1H NMR (500 MHz,
CDCl3) δH 7.54−7.40 (5H, m), 7.29−7.26 (2H, m), 7.18−7.15 (3H,
m), 5.30 (1H, dd, J = 6.2, 1.9 Hz), 3.56 (3H, m), 3.12 (1H, dd, J =
18.6, 6.2 Hz), 2.60 (2H, t, J = 7.8 Hz), 2.57 (1H, dd, J = 18.7, 1.9 Hz),
1.81 (1H, d, J = 15.1 Hz), 1.67 (1H, d, J = 15.2 Hz), 1.57 (3H, s),
1.64−1.20 (18H, m), 0.97 (3H, s); HR-ESIMS m/z 629.3051 [M +
Na]+ (calculated for C34H45F3NaO6 629.3060).
(R)-(2R,3R)-2-[(S)-2-Hydroxy-2-methyl-12-phenyldodecyl]-2-
methyl-5-oxotetrahydrofuran-3-yl 2-Methoxy-2-phenylace-
tate. The (R)-MPA derivative of ent-seco-plakortolide I (0.9 mg,
63%) was obtained as a colorless oil: 1H NMR (500 MHz, CDCl3) δH
7.44−7.35 (5H, m), 7.29−7.26 (2H, m), 7.19−7.16 (3H, m), 5.21
(1H, d, J = 5.2 Hz), 4.76 (1H, s), 3.38 (3H, s), 3.05 (1H, dd, J = 18.6,
6.1 Hz), 2.61 (2H, t, J = 7.8 Hz), 2.49 (1H, d, J = 19.3 Hz), 1.51 (1H,
d, J = 14.8 Hz), 1.51 (3H, s), 1.68−1.22 (18H, m), 1.41 (1H, d, J =
15.2 Hz), 1.12 (3H, s); 13C NMR (126 MHz, CDCl3) δC 173.6, 169.5,
143.1, 135.7, 129.5, 129.2, 128.5, 128.4, 127.6, 125.7, 88.4, 82.5, 76.6,
72.2, 57.3, 45.4, 43.5, 36.1, 35.9, 31.7, 30.2, 29.80, 29.76, 29.68, 29.5,
27.2, 24.8, 24.3, 23.7; HR-ESIMS m/z 561.3166 [M + Na]+
(calculated for C33H46NaO6 561.3187).
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures S1−S23. 1H and selected 2D NMR data for compounds
3, 4, 6a−c, and 7a−c. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*(J.-M.V.) Tel: +33-472258312. E-mail vatele@univ-lyon1.fr.
(M.J.G.) Tel: +61-7-3365 3605. Fax: +61-7-3365 4273. E-mail:
m.garson@uq.edu.au.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council, The University of
Queensland, and the French “Minister
̀
e de la Recherche et de
l’Enseignement Super
́
ieur” for financial support, and Prof. M.
G. Banwell (Australian National University) for valuable
discussions. We acknowledge an exchange of correspondence
with Prof. Y. Kashman.
REFERENCES
■
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1796
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