Bioinspired Total Synthesis of Delitschiapyrone A

Article abstract of DOI:10.1021/acs.orglett.8b01932

A bioinspired seven-step total synthesis of delitschiapyrone A was accomplished in 32% overall yield from commercially available 4-bromo-3,5-dimethoxybenzoic acid. The key step of the synthesis is an exclusively regioselective and diastereoselective reaction cascade consisting of the Diels-Alder reaction, α-ketol rearrangement, and cyclic hemiacetalization, achieved by simply stirring a heterogeneous mixture of two Diels-Alder substrates (putative biosynthetic intermediates) and water at 35 °C, directly furnishing the pentacyclic natural product in 75% yield.

Full text of DOI:10.1021/acs.orglett.8b01932

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Bioinspired Total Synthesis of Delitschiapyrone A
Kazuki Kurasawa,† Eunsang Kwon,*,‡ Shigefumi Kuwahara,† and Masaru Enomoto*,†
†Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki
Aza-Aoba, Aoba-ku, Sendai 980-8572, Japan
‡Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, 6-3 Aramaki Aza-Aoba,
Aoba-ku, Sendai 980-8578, Japan
S
* Supporting Information
ABSTRACT: A bioinspired seven-step total synthesis of
delitschiapyrone A was accomplished in 32% overall yield from
commercially available 4-bromo-3,5-dimethoxybenzoic acid. The
key step of the synthesis is an exclusively regioselective and
diastereoselective reaction cascade consisting of the Diels−Alder
reaction, α-ketol rearrangement, and cyclic hemiacetalization,
achieved by simply stirring a heterogeneous mixture of two Diels−
Alder substrates (putative biosynthetic intermediates) and water
at 35 °C, directly furnishing the pentacyclic natural product in
75% yield.
he Diels−Alder reaction has long been employed by
Scheme1.BiosyntheticPathwayfor1ProposedbyGunatilaka
and Coworkers4
T
organic chemists as an indispensable tool to obtain a
cyclohexene structural motif by virtue of its wide range of
applicability, as well as predictable stereoselectivity and
regioselectivity; its power has especially been exerted in the
total synthesis of natural products of high structural complex-
ity.1,2 Inadditiontoorganicchemists, itiswell-knownthatnature
alsomakesuseoftheDiels−Alderreaction forthebiosynthesisof
structurally diverse secondary metabolites, and the catalytic
processes of some enzymes (so-called “Diels−Alderases”) that
promotethispericyclicreactionhavegraduallybeenelucidatedat
the molecular level.3 Delitschiapyrone A (1) (see Figure 1), the
Figure 1. Structure of delitschiapyrone A (1).
biosynthesis of which was proposed to involve an intermolecular
Diels−Alder reaction, is a cytotoxic natural product (IC50: 12.3−
35.5 μM against several cancer cell lines) that was isolated by
Gunatilaka and co-workers from the fungus Delitschia sp.
FL1581.4 They determined its unique structure featuring an
unprecedented 6/6/5/7/6 pentacyclic ring system with five
contiguous stereocenters by X-ray crystallography, coupled with
ECD spectral analysis, and deduced its biosynthetic pathway, as
follows (see Scheme 1):
(2) the adduct 4 is transformed to 6/6/7/6 tetracyclic
intermediate 5 via α-ketol rearrangement; and
(1) twoputativeprecursorsnaphthoquinone2(dienophile)
and α-pyrone derivative 3 (diene)undergo the inter-
molecular Diels−Alder reaction to give cycloadduct 4;
Received: June 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01932
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Organic Letters
Letter
(3) cyclichemiacetalizationbetweentheC20hydroxylandthe
The preparation of the diene segment 3 (Scheme 3), which
contains a previously unreported 5,6-dialkylidene-5,6-dihydro-
C3 carbonyl in 5 delivers 1.
In support of this proposal, they isolated two known compounds,
6and7,5,6 fromthesamefungalculture;theputativedienophile2
is merely the 3-O-demethyl analogue of 6, and the diene 3 would
potentially be derivable from 7 via 1,4-conjugate elimination of
water, followed by oxidation at the C20 position.
Scheme 3. Preparation of Diene Segment 3
Inspection of the biosynthetic proposal led us to envisage that
the transformation from 4 to 1 would probably proceed with
exclusive stereoselection, regardless of whether it is an enzymatic
or nonenzymatic process, since the attack of the C13 carbon to
the C4 carbonyl in the α-ketol rearrangement of 4 would
inevitably occur from the bottom face (si face) of the carbonyl
group due to steric confinement imposed by the (2S,3S)-cis-
decalin system, and the cyclization of the C20 hydroxyl of 5 onto
the C3 carbonyl should occur also from the bottom face (re face)
of the carbonyl, because of the presence of the rigid (2R,4R)-
bicyclo[4.3.1]decane system in 5. The intermolecular Diels−
Alder reaction (2/3 → 4), on the other hand, has the possibility
of affording eight isomers, including 4 (see p S41 in the
Supporting Information (SI)), depending on its regio-, endo/
exo-, and diastereofacial selectivities. In this article, we describe
the first total synthesis of 1 in 32% overall yield from a
commercially available benzoic acid derivative through only
seven steps, which involve an efficient cascade sequence initiated
by the Diels−Alder reaction between 2 and 3.
2H-pyran-2-one unit, commenced with palladium-catalyzed
cross-couplingofknownbromide14with(E)-but-1-enylboronic
acid to give 15 in 94% yield.11 Subjecting 15 to the Sharpless
asymmetric dihydroxylation conditions using AD-mix-α deliv-
ered diol 16, whose enantiomeric excess was determined to be
99% by analyzing the 1H NMR spectra of the corresponding (R)-
and (S)-20-mono-MTPA esters. The diol 16 was converted to
cycliccarbonate17 andthenexposed toLiHMDSinTHFat−78
°C, whichinducedsmooth1,4-conjugateeliminationtofurnish3
in 75% yield (53% overall yield from 14 in four steps) as a single
geometrical isomer.12 The E-geometry of its C17−C19 double
bond was assigned by observing diagnostic NOE correlations, as
depicted in Scheme 3.
Scheme 2 illustrates the preparation of the dienophile 2 from
commerciallyavailable 4-bromo-3,5-dimethoxybenzoic acid(8).
Scheme 2. Preparation of Dienophile Segment 2
The final stage of our total synthesis of 1, which involves the
Diels−Alder assembly of the two segments, 2 and 3, is shown in
Scheme 4. To begin with, a solution of 2 and 3 (4 equiv) in
Scheme 4. Endgame of the Total Synthesis of 1
One-carbon homologation of 8 by the standard Arndt−Eistert
sequence gave 9,7 which was then subjected to the Suzuki−
Miyauracouplingwithtriethylboranetoafford10.8 Treatmentof
10 with AcCl (1.2 equiv) in CH2Cl2 at reflux in the presence of
AlCl3 (2.4 equiv) brought about its Friedel−Crafts acetylation to
11 and selective removal of the methoxy group ortho to the acetyl
group, furnishing 12 in 72% yield.9 Finally, the Dieckmann
condensation of the keto ester 12, followed by air oxidation of
intermediate 13 in one pot, gave 2 in 42% overall yield from 8 via
six operational steps.10
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toluene was stirred at 35 °C under a nitrogen atmosphere. The
Diels−Alder reaction proceeded, albeit sluggishly, and the
desired cycloadduct 4, the structure of which was determined
by X-ray crystallography, was isolated in 15% yield after 2.5 days
of stirring, with ca. 70% of the starting quinone 2 recovered.
Interestingly, 4 was obtained as a single isomer, and none of the
other regioisomers and stereoisomers were detected in the crude
reaction mixture. Furthermore, close examination of the
byproducts in this reaction revealed that our final synthetic
target1wasalsoproduced(6% isolatedyield), indicatingthatthe
three reactions (Diels−Alder reaction, α-ketol rearrangement,
and cyclic hemiacetalization) could be effected as a cascade
sequence.13 When the reaction was conducted at 50 °C, the
starting material 2 was consumed completely after 2 days,
affording 4 in an improved yield of 48%, along with 8% of 1,
although heating the reaction mixture at reflux led to the
formation of a complex mixture. Next, with the intention of
increasing the reaction rate, the crystalline quinone 2 and the oily
diene 3 were mixed under solvent-free (neat) conditions, and the
resulting viscous suspension was stirred at 40 °C for 1.5 days,
which provided 1 in 38% yield, together with a 42% yield of 4.
Finally, a much improved transformation of 2 into 1 was realized
byaddingwatertotheheterogeneousmixtureof2and3andthen
stirring the mixture at 35 °C for 2.5 days, furnishing 1 in a
satisfactory yield of 75%, along with the intermediary cyclo-
adduct 4 in 22% yield.14 The 1H and 13C NMR spectra of 1 were
identicalwiththoseofnaturaldelitschiapyroneA,andthespecific
rotation of 1 ([α]D +124 (c 0.44, MeOH)) showed good
agreement with that reported for the natural product ([α]D +121
(c 0.12, MeOH)).4 Water has been documented to promote
various organic reactions, including the Diels−Alder reaction
and α-ketol rearrangement.15 The much more efficient
conversion of 2/3 into 1 in the presence of water, rather than
in toluene or under the neat conditions, seems to indicate that
this reaction is one such example.
based on the DFT-optimized structure of 3 at the B3LYP/6-
31G(d) level of theory (Figure 2b). In this generally preferred
endo transition state, the dienophile 2 approaches the diene 3,
which is in its preferred conformation to minimize 1,3-allylic
strain,17 fromthestericallyless-hinderedupperface.Anattractive
electronic interaction between the hydrogen atom of the C20
hydroxyl of 3 (δ+) and the oxygen atom of the C1 carbonyl of 2
(δ−), which was suggested by the calculated electrostatic
potentials of 2 and 3 (see p S56 in the SI), acts synergistically
to enhance the diastereofacial selectivity and facilitate the
intermolecular reaction.18 It is worth mentioning that the
attempted Diels−Alder reaction between 2 and ( )-20-O-
acetyl-3 gave a complex mixture, which shows the crucial role of
the C20 hydroxyl of 3 in this Diels−Alder reaction.19
In summary, a biomimetic total synthesis of the cytotoxic
fungal metabolite delitschiapyrone A (1) has been accomplished
inanexcellentoverallyieldof32%fromcommerciallyavailable4-
bromo-3,5-dimethoxybenzoic acid (8) through seven steps. The
notable features ofthe synthesisare (1)the dienophilesegment 2
was prepared from 8 via a six-step sequence involving two one-
pot processes (10 → 12 and 12 → 2); (2) the diene segment 3
was obtained as a single geometrical isomer by 1,4-conjugate
elimination of the cyclic carbonate 16; and (3) the Diels−Alder
reaction of the juglone derivative 2 with the diene 3, followed by
concomitant α-ketol rearrangement and cyclic hemiacetaliza-
tion, proceeded with exclusive regioselectivity and stereo-
selectivity, directly affording 1 in a good isolated yield of 75%.
It is remarkable that the Diels−Alder-initiated reaction cascade
was realized in a surprisingly efficient manner as a heterogeneous
mixture with water (the solvent used by nature) at 35 °C (nearly
ambient temperature), which would suggest the possibility that
the final stage of the biosynthesis of delitschiapyrone A might
occur nonenzymatically, even in nature.
ASSOCIATED CONTENT
* Supporting Information
■
S
In the above-described cascade sequence, the desired final
product 1 was obtained in 75% yield together with a 22% yield of
the Diels−Alder adduct 4, which means that the Diels−Alder
process proceeded regioselectively and diastereoselectively in
almost quantitative yield (75% plus 22%). The regioselectivity of
this Diels−Alder reaction was rationalized by calculating the
energies and coefficients of the frontier orbitals of 2 and 3, which
indicated that the LUMO of 2 would interact with the HOMO of
3 and that C2 and C3 of 2 would make bonds with C19 and C13
of 3, respectively (see pp S55−S56 in the SI).16 The
diastereofacial selectivity of the cycloaddition was, on the other
hand, interpreted by assuming a transition state (Figure 2a),
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01932.
Experimental procedures, characterization data, NMR
spectra for new compounds, and theoretical calculations
(PDF)
Accession Codes
CCDC 1554823 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ekwon@m.tohoku.ac.jp (E. Kwon).
*E-mail: masaru.enomoto.a2@tohoku.ac.jp (M. Enomoto).
ORCID
Masaru Enomoto: 0000-0001-6342-217X
Author Contributions
M.E. and S.K. designed the synthetic route and wrote the
manuscript. K.K. conducted the synthetic experiments, with the
aid of M.E. E.K. performed the X-ray crystallographic analysis, as
well as computational studies, and wrote the manuscript.
Figure 2. (a) Plausible transition state for the Diels−Alder reaction
between 2 and 3. (b) DFT-optimized structure of 3 at the B3LYP/6-
31G(d) level of theory.
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(16) For an example of Diels−Alder reaction of juglone (5-hydroxy-
1,4-benzoquinone) with an unsymmetrical 1,3-diene having a
substitution pattern analogous to that of 3, see: Nechepurenko, I. V.;
Shul’ts, E. E.; Tolstikov, G. A. Russ. J. Org. Chem. 2001, 37, 1276−1283.
(17) Broeker, J. L.; Hoffmann, R. W.; Houk, K. N. J. Am. Chem. Soc.
1991, 113, 5006−5017.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI (Grant
No. 16K07708), by JSPS Core-to-Core Program, A: Advanced
Research Networks entitled “Establishment of International
Agricultural Immunology Research-Core for a Quantum
Improvement in Food Safety”, and by the Platform Project for
Supporting Drug Discovery and Life Science Research funded by
the Japan Agency for Medical Research and Development
(AMED). We thank Ms. Yuka Taguchi (Tohoku University) for
her help with NMR and MS measurements.
̈
(18) For analogous reactions, see: (a) Adam, W.; Glaser, J.; Peters, K.;
Prein, M. J. Am. Chem. Soc. 1995, 117, 9190−9193. (b) Nicolaou, K. C.;
Lim, Y. H.; Becker, J. Angew. Chem., Int. Ed. 2009, 48, 3444−3448.
(c) Nicolaou, K. C.; Becker, J.; Lim, Y. H.; Lemire, A.; Neubauer, T.;
Montero, A. J. Am. Chem. Soc. 2009, 131, 14812−14826.
1
(19) Judging from the phenolic OH proton region of the H NMR
spectrum, the crude reaction mixture seemed to contain at least four
isomeric cycloadducts.
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