Total Synthesis and Absolute Stereochemical Assignment of the Insecticidal Metabolites Yaequinolones J1 and J2

Article abstract of DOI:10.1021/acs.orglett.8b01701

A highly stereocontrolled total synthesis of (-)-yaequinolone J1 and (+)-yaequinolone J2 was accomplished using an Evans auxiliary to establish a syn-diol unit in an acyclic appendage to a preformed benzopyran core bearing a homoprenyl group. The first to

Full text of DOI:10.1021/acs.orglett.8b01701

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis and Absolute Stereochemical Assignment of the
Insecticidal Metabolites Yaequinolones J1 and J2
Vito Vece, Shashidhar Jakkepally, and Stephen Hanessian*
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Department of Chemistry, Universite de Montreal, P.O. Box 6128, Succ., Centre-ville, Montreal, Quebec, Canada, H3C 3J7
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* Supporting Information
ABSTRACT: A highly stereocontrolled total synthesis of
(−)-yaequinolone J1 and (+)-yaequinolone J2 was accom-
plished using an Evans auxiliary to establish a syn-diol unit in
an acyclic appendage to a preformed benzopyran core bearing
a homoprenyl group. The first total synthesis of a complex
member of this family of 3,4-dioxygenated 3,4-dihydro 4-aryl
quinolin-2-(1H)-ones also allowed the assignment of absolute
stereochemistry, thereby suggesting the same for several members of this family of biogenetically related alkaloids hitherto
reported with relative configurations of stereogenic carbons for some and absolute assignments relying on empirical data for
others.
manifested in the patent literature.7 The stereochemistry of the
lkaloids comprising the quinolone core isolated primarily
Afrom terrestrial plants are among the most abundant majority of these fascinating metabolites has been studied by
detailed NMR spectroscopic methods.6,8 In some cases ECD
(electronic circular dichroism) in conjunction with theoretical
calculations have been used to propose absolute stereo-
chemistry.4,9,11 However, even when X-ray crystal structures
were available, only relative stereochemistries could be
assigned.10,11
biologically relevant natural products.1 Among this important
family is a new group of oxygenated congeners that have
recently emerged with diverse biological activities particularly
as insecticides2,3 as well as antiviral4 and anticancer agents.5
The first report of such metabolites isolated from Penicillium
sp. NTC-47 revealed the existence of 3,4-dioxygenated 3,4-
dihydro 4-aryl quinolinones, for which only relative stereo-
chemistries were assigned.2 In the ensuing 20 years since the
initial report, a plethora of 3,4-dioxygenated 3,4-dihydro 4-aryl
quinolin-2-(1H)-ones and their 5-hydroxy variants (Figure 1)
have been isolated from plant and marine fungi and their
biological activities evaluated.6 Interest in this family of natural
products has grown exponentially over the past 20 years as
Elegant biosynthetic studies have revealed that the 4-
methoxyphenyl (or phenyl) dihydroquinolone core originates
from anthranilic acid and O-methyl tyrosine (or tyrosine)
which involve discrete intermediates that are hydroxylated and
eventually prenylated at a later stage to give a variety of prenyl
and prenyl derived oxygenated heterocycles at C-612 (Figure
1).
In spite of their biological activities,6 efforts toward the total
synthesis of this class of 3,4-dioxygenated 3,4-dihydroquino-
lones in general have been sparse.13 So far, among these
fascinating compounds, only a total synthesis of racemic
yaequinolone A2,3 the structurally simplest member of this
family, has been reported in 2009 by Pan and co-workers14
(Figure 1).
In 2005, Tomoda and co-workers reported the isolation of
two novel metabolites named yaequinolones J1 (1) and J2 (2)
from a culture strain of Penicillium sp. FKI-2140, isolated from
a soil sample collected at Ishigakijima Island, Okinawa
Prefecture, Japan15 (Figure 1). These metabolites showed
growth inhibitory activity against Artemia salina (brine shrimp)
with the same MIC value of 6.25 μg/mL. Extensive NMR
1
studies including H−1H COSY and HMBC correlations, as
well as NOE measurements, designated the relative stereo-
chemistry of 1 as 3R*4R*3″S*. Similar analysis of 2 led to an
Figure 1. Revised absolute configuration of (−)-yaequinolone J1 (1)
and (+)-yaequinolone J2 (2) and general structure of 3,4-
dioxygenated 3,4-dihydro 4-aryl quinolin-2(1H)-ones (yaequinolone
A2, R1 = H, R2 = OMe, R3 = R4 = H).
Received: May 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01701
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
identical relative stereochemistry except for 3″ which was
determined to be 3″R*. Thus, the two metabolites differed
only in the relative stereochemistry of the pyranyl tertiary
carbon bearing the methyl group.
Scheme 2. Synthesis of Aniline Derivative 9
Herein we report the first asymmetric total synthesis of
yaequinolones J1 (1) and J2 (2) as well as the establishment of
their absolute stereochemistries. In considering various bond
disconnections toward suitable building blocks, we were
cognizant that the presence of a tertiary benzylic hydroxyl
group could easily form stabilized cations leading to β-
elimination and the formation of byproducts depending on the
choice of reagents and reaction used. Moreover, we
appreciated the challenge involved in securing the syn-
stereochemistry of the C-3/C-4 diol unit with the required
absolute configurations.
Based on the assumption that the relative stereochemistries
as indicated by Tomoda and co-workers15 corresponded to the
proposed structures and in the absence of other confirming
data, we completed the total synthesis of 3R, 4R, 3″S
(+)-yaequinolone J1, only to realize that we had produced
the enantiomer (ent-1) as indicated from the positive optical
rotation value (see Supporting Information (SI)). With this
knowledge, which is in full agreement with the proposals
suggested for similar natural products of this family relying on
ECD spectra,4,9,11 we resumed our work toward the total
synthesis of the stereochemically revised 3S, 4S, 3″R isomer.
For strategic considerations we chose to first address the
synthesis of the homoprenylated pyran ring comprised within
the B/C ring system of the target yaequinolones (Scheme 1).
Facile ortho-Claisen rearrangement20 occurred in refluxing
toluene to afford 10 which was converted to the N-Boc
protected alcohol 11. Swern oxidation led the aldehyde 12
which was subjected to an aldol reaction according to Evans16
with the oxazolidinone 1321 derived from (S)-phenylalanine to
afford a 1:1 inseparable mixture of diastereoisomers 14
differing in the configuration of the pyranyl tertiary methyl
group (Scheme 3).
Scheme 3. Synthesis of Diols 15a and 15b
Scheme 1. Retrosynthetic Disconnection of Yaequinolones
a
J1 (1) and J2 (2)
a
Asterisk denotes epimeric carbon.
Retrosynthetically this could be accomplished through an
ortho-Claisen rearrangement from I to II. Critical to the
success of this strategy was to develop stereocontrolled
reactions that would include two vicinal stereogenic carbon
atoms bearing an O-methyl group and a tertiary benzylic
alcohol as in IV. We considered that the Evans chiral auxiliary-
mediated aldol reaction16 to be admirably suited for the
elaboration of C-2 bearing the O-methyl group with the
desired 3S stereochemistry of the two natural products.
Starting with 6-hydroxy-2-nitrotoluene 3, protection as the
OTBS ether 4, bromination to 5, and conversion to the
silyloxymethyl intermediate 617proceeded in near-quantitative
yield. A CuI catalyzed alkylation with the homoprenyl reagent
718afforded the ether 8. Reduction of the nitro group in the
presence of Fe powder19 afforded the aniline 9 in high yield
(Scheme 2).
Remarkably, only one syn-aldol diol was produced with the
desired 3S-configuration at the C-3 methoxy-bearing carbon.
Reductive cleavage of the oxazolidinone22 afforded the two
diastereoisomers 15a and 15b in equal amounts which were
separated by column chromatography (Scheme 3).
Isomer 15a was converted to the ketone 16 in high overall
yield. An X-ray crystal structure provided definitive proof of
B
DOI: 10.1021/acs.orglett.8b01701
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
absolute 3″R stereochemistry (Scheme 4). Treatment of the
ketone 16 with p-methoxyphenyl magnesium bromide was
melanoma A375 cell line respectively as well as 3.38 and 4.08
μM against the colorectal HCT116 cell line.
In conclusion, we report the first asymmetric total synthesis
of yaequinolones J1 (1) and J2 (2) accomplished in 18 steps
with a global yield of 11% for both the natural products. With
the establishment of their absolute stereochemical assignment
through a total synthesis, other members of this biosyntheti-
cally related family of metabolites whose stereochemistries
were previously assigned on a relative basis can now be
configurationally correlated.
Scheme 4. Synthesis of Yaequinolone J1 (1) from 15a
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01701.
Synthetic schemes for 1 and 2, detailed experimental
procedures in which IUPAC nomenclature and number-
ing was adopted, spectral data and X-ray crystallographic
data (PDF)
Accession Codes
CCDC 1826666−1826667 and 1826761 contain the supple-
mentary 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 Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
remarkably stereoselctive affording the desired 4S tertiary
alcohol 17 in 77% yield along with 11% of elimination product
18. It was imperative to conduct this reaction at −78 °C to
minimize the β-elimination of the OTBDPS group. There
remained cleaving the primary alcohol to afford 19 and finding
a suitable oxidation method that would give an intermediate N-
protected hemiaminal which could be further oxidized to the
desired N-Boc dihydroquinolin-2-one 20. Among the many
oxidants that we tried (PDC, Corey−Schmidt, PCC), none
were as effective and selective as the TEMPO, PhI(OAc)2
combination.23 This oxidizing system initially gave a hemi-
aminal intermediate which could be detected by NMR analysis
after 3 h before further oxidation to the lactam took place. An
X-ray crystal structure provided definitive proof of the global
structure and, importantly, the expected S-stereochemistry at
the benzylic carbon atom. To the best of our knowledge this
TEMPO, PhI(OAc)2 reagent combination has not been used
for the direct synthesis of an N-Boc lactam from a primary
alcohol. Being weary of the lability of the tertiary benzylic
hydroxyl group under acidic conditions, and the ever-present
problem of β-elimination, we were pleased that heating a
dioxane−water solution24 of 20 led to 1 as a white amorphous
■
Corresponding Author
*E-mail: stephen.hanessian@umontreal.ca.
ORCID
Stephen Hanessian: 0000-0003-3582-6972
Notes
The authors declare no competing financial interest.
The numbering used in the manuscript was the same as that in
the original publication (ref 15) for consistency and in related
papers and reviews (ref 6).
ACKNOWLEDGMENTS
We thank NSERC for financial assistance. X-ray crystal
structures were done in the X-ray facility at the Universite
■
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de Montreal. We are grateful to Jin Ting, Hugo Lavoie, and
Marc Therrien at IRIC, for performing the cell proliferation
tests. Dedicated to Professor David A. Evans for his scholarly
and timely contributions to advance the science of asymmetric
synthesis and catalysis.
solid in nearly quantitative yield; [α]25 = −68.1° (c = 1.3,
DEDICATION
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EtOH); reported15 [α]23 = −65.6° (c = 0.1, EtOH).
Starting with the C-3″Depimeric intermediate 15b, we also
completed the total synthesis of (+)-yaequinolone J2, obtained
as a white amorphous solid (see SI); [α]25D = +187.1° (c = 1.1,
Dedicated to Professor David A. Evans for his scholarly and
timely contributions to advance the science of asymmetric
synthesis and catalysis.
EtOH), reported15 [α]23 = +181.7° (c = 0.1, EtOH).
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D
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highly promising EC50 values of 8.24 and 3.73 μM against a
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