Biomimetic Synthesis Enables the Structure Revision of Littordials e and F and Drychampone B

Article abstract of DOI:10.1021/acs.orglett.0c03156

Structural reassignments for littordial E, littordial F, and drychampone B are proposed on the basis of consideration of their biosynthetic origin. The key step in the proposed biosynthesis of each of these meroterpenoids is an intermolecular hetero-Diels-Alder reaction between an o-quinone methide and caryophyllene or humulene. Biomimetic total synthesis of the natural products gave sufficient material to allow their structure revision by NMR studies.

Full text of DOI:10.1021/acs.orglett.0c03156

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Letter
Biomimetic Synthesis Enables the Structure Revision of Littordials E
and F and Drychampone B
́
Tomas Vieira de Castro, Oussama Yahiaoui, Ricardo A. Peralta, Thomas Fallon, Victor Lee,
and Jonathan H. George*
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ABSTRACT: Structural reassignments for littordial E, littordial F, and drychampone B are proposed on the basis of consideration of
their biosynthetic origin. The key step in the proposed biosynthesis of each of these meroterpenoids is an intermolecular hetero-
Diels−Alder reaction between an o-quinone methide and caryophyllene or humulene. Biomimetic total synthesis of the natural
products gave sufficient material to allow their structure revision by NMR studies.
espite the availability of increasingly powerful spectro-
Dscopic tools, the accurate characterization of complex
natural products remains challenging. In particular, structural
assignments based primarily on the analysis of 2D NMR
spectra are vulnerable to human error. We believe that
consideration of the probable biosynthesis of a natural product
can greatly assist in its initial structural assignment or its
subsequent reassignment.1 In addition, total synthesis con-
tinues to play an important role in natural product structure
revisions,2 alongside modern DFT predictions of NMR
spectra.3 Herein we apply biosynthetic analysis and biomimetic
total synthesis to revise the structures of three dubiously
assigned meroterpenoid natural products: littordials E and F
and drychampone B.
The isolation of littordials A−E (1−5) (Figure 1) from the
leaves of Psidium littorale (commonly known as strawberry
guava) was reported in 2019,4 followed by the discovery of
littordial F (6) from the same plant later that year.5 These
meroterpenoids are presumably biosynthesized via the union
of (−)-caryophyllene (9) and a diformylphloroglucinol
Figure 1. Littordials A−F, with biosynthetically inspired structure
derivative. Littordials A−D all feature a 6−6−9−4 ring system
revisions suggested for littordials E and F.
that could arise from a hetero-Diels−Alder reaction between
an o-quinone methide6 (o-QM) and the reactive trans Δ4,5
alkene of caryophyllene. Indeed, similar cycloadditions have
Received: September 19, 2020
been achieved in the biomimetic synthesis of several
caryophyllene-derived meroterpenoids.7 However, the pro-
posed seven- and eight-membered rings of littordials E and F
(highlighted in blue in Figure 1) are biosynthetically
implausible. On the basis of our biosynthetic analysis, we
speculated that the true structure of littordial E (7) is probably
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Scheme 1. Biomimetic Synthesis of Littordials A, B, C, E, and F
a diastereomer of littordial C (3) and that littordial F (8) is a
diastereomer of littordials A and B (1 and 2). To verify this
hypothesis, we planned to synthesize the hypothetical
structures 7 and 8 from caryophyllene and the appropriate o-
QM intermediates. In addition to providing samples of
littordials E and F for further detailed spectroscopic analysis,
their synthesis via a biomimetic Diels−Alder-based strategy
would be strong evidence in favor of the proposed structural
reassignments.
spectra strongly support the reassignment of littordial E from
structure 5 to 7 (Figure 2). The key misassignment in the
The biomimetic synthesis of the meroterpenoids guajadial
(12) and psidial A (13),8 which are closely related to the
littordials, via an intermolecular hetero-Diels−Alder reaction
between (−)-caryophyllene (9) and an o-QM was previously
investigated by Lee et al. (Scheme 1). They showed that
condensation of commercially available diformylphloroglucinol
(10)9 with benzaldehyde in water gave o-QM 11, which
underwent a hetero-Diels−Alder reaction with caryophyllene
to give a mixture of 12, 13, and a (yet to be isolated)
diastereomer 14 in a combined yield of 25%. Under the
optimized conditions, this multicomponent cascade reaction
was conducted in an aqueous solution containing 5% w/w
PEG-600/α-tocopherol-based diester of sebacic acid (PTS) as
a surfactant. We reasoned that replacement of benzaldehyde
with hexanal in this cascade reaction would allow the synthesis
of littordial C (3) and the revised littordial E (7). Thus,
condensation of 10 with hexanal in the presence of 9 and
catalytic ethylenediammonium diacetate (EDDA) in hexa-
fluoroisopropanol (HFIP) gave a 40% yield of 3 and a 14%
yield of 7. These conditions were previously used in Cramer’s
one-step synthesis of another related meroterpenoid, psiguadial
B.10
Figure 2. Key 2D NMR correlations in the structure revision of
littordial E.
original isolation work is at H-14′. The claimed COSY
correlation between one of the H-14′ signals (δH = 0.77) and
H-5 (δH = 2.17) is difficult to assess because of overlapped
peaks around H-5. Although we observe a weak correlation
from this region to H-14′, the proximity of one of the H-10′
signals (δH = 2.18) makes this assignment questionable.
Additionally, in our spectra we observe a COSY correlation in
the region of δH = 1.41−1.45 to H-14′ (δH = 0.77). Signals
from this region are assigned to the second proton of C-10′
(δH = 1.43) and H-2 (δH = 1.44). Considering that a COSY
correlation from H-2 to H-14′ would be impossible, this
correlation can only arise from the coupling of the H-10′
proton to H-14′. These two couplings, δH = 2.18 to δH = 0.77
and δH = 1.43 to δH = 0.77, therefore imply a correlation of H-
The 1D and 2D NMR spectra of synthetic littordial E (7) in
CDCl3 matched the data for the isolated natural product. It is
mechanistically implausible that the originally proposed
littordial E structure 5 could form under the reaction
conditions. Furthermore, close examination of the 2D NMR
B
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10′ to H-14′ rather than H-14′ to H-5, which is only possible
with the revised structure 7. Further key HMBC and COSY
correlations (Figure 2) confirm the 6−6−9−4 ring system of 7.
The NOESY spectrum of 7 in CDCl3 was again difficult to
interpret because of the overlapped region around the key H-5
resonance. However, the NOESY spectrum of 7 in C6D6
showed correlations between H-9′ (δH = 2.45) and Me-14
Caryophyllene can adopt four conformations in solution,
termed αα, αβ, βα, and ββ according to the relative disposition
of the exocyclic alkene and the vinyl methyl substituent. NMR
studies have shown that caryophyllene exists as a 48:28:24 αα/
βα/ββ mixture.12 While conformers αα and βα are known to
be in rapid exchange, their exchange with the ββ conformer is
relatively slow, with an experimentally determined barrier of 68
kJ mol−1. In line with previous studies on the biomimetic
synthesis of guajadial and psidial A,8 we propose that littordials
B and C (2 and 3) and littordials E and F (7 and 8) arise from
cycloaddition between o-QMs 15/16 and the βα conformation
of 9 while littordial A (1) is formed from the ββ conformation
(Figure 4).
(δH = 0.76) and between H-5 (δH = 2.13) and H-1 (δH
=
2.04). Littordial E (7) therefore has the same 6−6−9−4 ring
system and relative configuration as guajadial (12).
Our analysis of the 2D NMR spectra for synthetic 3 agreed
with the original structure elucidation for littordial C,4 and this
was confirmed by single-crystal X-ray crystallography (Figure
3; see the Supporting Information).
Figure 3. X-ray crystal structure of littordial C (for clarity, only H
atoms at stereocenters are shown).
The use of butanal as the aldehyde component in the
cascade reaction with 9 and 10 allowed the synthesis of the
revised structure of littordial F (8) in 3% yield alongside
littordials A (1) and B (2) as an inseparable mixture (5:1 ratio
in favor of 2) in a combined yield of 42% (Scheme 1). Since
the structure of 1 was previously established by single-crystal
X-ray crystallography4 and the structure of 2 is also not in
doubt because of its close similarity to 3, we focused our
1
attention solely on the characterization of 8. The H and 13C
NMR spectra of 8 are almost identical to the corresponding
spectra of 7, except for two additional methylene groups in the
n-pentyl side chain appended to C-9′ of 7 compared with the
n-propyl substituent of 8. Thus, we propose that the revised
littordial F structure 8 has the same 6−6−9−4 ring system and
the same relative configuration as 7 and 12. This assignment is
also supported by 2D NMR studies (see the Supporting
Information for full details). The formation of the originally
assigned littordial F structure 6 under our reaction conditions
is mechanistically implausible. Although the proposed littordial
F structure 6 was supported by predicted 13C NMR data
calculated using DFT methods, the conformational flexibility
of this compound makes such a calculation potentially
misleading.5
The absolute configuration of isolated littordial A (1) was
initially assigned by single-crystal X-ray diffraction analysis with
Ga Kα radiation, which was supported by a comparison
between experimental and calculated CD spectra for all of the
littordials.4,5 This configuration arises from the more common
(−) enantiomer of caryophyllene. As expected, the CD spectra
of synthetic littordials C, E, and F (also derived from
(−)-caryophyllene) matched those of the isolated natural
products. However, our measured optical rotations differed
significantly from those of the reported natural products, which
could be due to the presence of minor diastereomeric
impurities in either the synthetic or natural samples.11
Figure 4. Plausible transition states leading to littordials A, B, and F.
Computational modeling was used to assess the possible
cycloaddition pathways leading to littordials A, B, an F and an
additional diastereomer analogous to 14. Calculations were
performed using DFT with the M06-2X functional and the 6-
31+G(d) basis set for geometry optimizations and frequency
analysis, with single-point energies calculated at the 6-
311+(d,p) level.
Given that caryophyllene has four possible conformers and
that o-QM 16 may be formed as either the E or Z isomer and
taking into account the endo/exo stereoselectivity, there are 16
possible reaction pathways, of which those involving the
nonpopulated αβ conformer of caryophyllene are discounted.
o-QMs E-16 and Z-16 are calculated to have essentially the
same stability (ΔG = −1.2 kJ mol−1), and any E/Z selectivity
in the formation 16 is unknown, so both isomers must be
considered as viable reactants. The lowest-energy TSs leading
to littordials A, B, and F are illustrated in Figure 4. This
analysis reveals that in general a concerted Diels−Alder
cycloaddition between 9 and 16 is energetically feasible
under the reaction conditions. The Diels−Alder transition
C
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structures are characteristically highly asynchronous, with C−
O forming bond lengths ranging from 2.64 to 2.96 Å.13
Because of the isomeric complexity of both reactants, the
high reactivity of o-QM intermediates, and the challenges of
experimental analysis and purification, caution must be taken
in rationalizing the product distributions. The lowest-energy
pathway (caryophyllene-ββ−Z-o-QM−exo-TS) has a calcu-
lated barrier of ΔG⧧ = 40.9 kJ mol−1. This leads to littordial A
(isolated as a minor isomer), which is consistent with its
arising from the minor ββ conformer of caryophyllene. The
formation of littordial B from the E-configured o-QM has the
predicted lowest-energy pathway shown, with a barrier of 51.9
kJ mol−1, whereas littordial F forms from the Z-configured o-
QM with a predicted barrier of 49.6 kJ mol−1. Notably, the
lowest-energy pathway leading to the diastereomer analogous
to 14 (caryophyllene-ββ−Z-o-QM−endo-TS, not shown) has a
barrier of ΔG⧧ = 55.6 kJ mol−1, perhaps explaining its absence
synthetically and in isolation studies.
The isolation of three racemic meroterpenoids, drycham-
pones A−C, from the Chinese fern Dryopteris championii was
reported in 2016.14 Although the drychampones are most
likely derived from a hetero-Diels−Alder reaction between an
o-QM and the reactive Δ1,2 alkene of humulene (19),15
drychampone B (17) was surprisingly assigned a Z
configuration for its Δ4,5 alkene on the basis of a claimed
3J4−5 coupling constant of <10 Hz (Figure 5). However, since
Scheme 2. Biomimetic Synthesis and Structure Revision of
Drychampone B
the advanced spectroscopic techniques at the disposal of
organic chemists, often the interpretation of sophisticated
spectroscopic data is subject to human error. We believe that
the structure elucidation of a new natural product should not
be based only on spectroscopic analysis; it is equally important
that the putative structure should also be supported by a
plausible biosynthetic hypothesis. The combination of these
two approaches will minimize the number of incorrect
structural assignments.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03156.
Experimental procedures, NMR spectra, CD spectra,
single-crystal XRD data, and computational methods for
all new compounds (PDF)
Accession Codes
CCDC 2017518 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
Figure 5. Proposed structure revision for drychampone B.
1
the H NMR signals for H-4 and H-5 of drychampone B in
CDCl3 are overlapped and cis-humulenes are scarce in nature,
we proposed that 18 (with an E configuration of its Δ4,5
alkene) is the true structure of drychampone B.
AUTHOR INFORMATION
Corresponding Author
■
The synthesis of the revised structure of drychampone B
(Scheme 2) started from readily available 10, which was also
used in our littordial syntheses. Reduction of the aldehyde
functional groups of 10 with NaBH3CN under acidic
conditions gave dimethylphloroglucinol (21),16 which under-
went Friedel−Crafts acylation with butyryl chloride to give
acylphloroglucinol 22.17 Oxidation of 22 using Ag2O and
TEMPO7d then generated o-QM 20, which was trapped in situ
with 19 to give drychampone B (18) in 17% yield. The 1D and
2D NMR spectra of synthetic 18 in CDCl3 fully matched the
natural product isolation data for drychampone B. Further-
Jonathan H. George − Department of Chemistry, University of
Adelaide, Adelaide, SA 5005, Australia; orcid.org/0000-
0002-7330-2160; Email: jonathan.george@adelaide.edu.au
Authors
́
Tomas Vieira de Castro − Department of Chemistry, University
of Adelaide, Adelaide, SA 5005, Australia
Oussama Yahiaoui − Department of Chemistry, University of
Adelaide, Adelaide, SA 5005, Australia
Ricardo A. Peralta − Department of Chemistry, University of
Adelaide, Adelaide, SA 5005, Australia
Thomas Fallon − Department of Chemistry, University of
Adelaide, Adelaide, SA 5005, Australia
Victor Lee − Department of Chemistry, University of Oxford,
Oxford OX1 3TA, U.K.; orcid.org/0000-0002-4032-6481
1
more, the H NMR spectrum of 18 in C6D6 clearly showed a
3J4−5 coupling constant of 15.8 Hz, consistent with an E
configuration for the Δ4,5 alkene.
In conclusion, we have applied biosynthetic speculation to
guide the structure revision of littordials E and F and
drychampone B. The reassignments were confirmed through
biomimetic total synthesis and NMR studies. Even with all of
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03156
D
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by an Australian Research Council
Future Fellowship awarded to J.H.G. (FT170100437).
■
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