Synthesis of aspidodispermine via pericyclic framework reconstruction

Article abstract of DOI:10.1021/acs.orglett.0c01242

A divergent approach to the pyrroloquinoline scaffold as present in the class of Aspidosperma alkaloids was developed. As a case study, abundant and renewable nicotinic acid was transformed via pericyclic framework reconstruction into aspidodispermine, a unique member of pyrroloquinoline alkaloids. The sequence comprises a [2 + 2]-photocycloaddition, a Ramberg-B?cklund contraction, and a strain-promoted formal electrocyclic rearrangement of a bicyclo[2.2.0]hexene and is potentially extendable to pyrroloindole scaffolds as present in the ibophyllidine alkaloids.

Full text of DOI:10.1021/acs.orglett.0c01242

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Synthesis of Aspidodispermine via Pericyclic Framework
Reconstruction
Franziska Reuß and Philipp Heretsch*
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ABSTRACT: A divergent approach to the pyrroloquinoline scaffold as present in
the class of Aspidosperma alkaloids was developed. As a case study, abundant and
renewable nicotinic acid was transformed via pericyclic framework reconstruction
into aspidodispermine, a unique member of pyrroloquinoline alkaloids. The
̈
sequence comprises a [2 + 2]-photocycloaddition, a Ramberg−Backlund
contraction, and a strain-promoted formal electrocyclic rearrangement of a
bicyclo[2.2.0]hexene and is potentially extendable to pyrroloindole scaffolds as
present in the ibophyllidine alkaloids.
As a showcase of this strategy, aspidodispermine (1)
presented itself as a unique and yet unmet synthetic challenge.
Structurally, 1 is the only member of the Aspidosperma
alkaloids which carries a hydroxy group instead of the typical
angular ethyl group at C5 (Scheme 1A). After a first tentative
he Aspidosperma and ibophyllidine alkaloids are closely
Trelated classes of natural products which possess either a
pyrroloquinoline or a pyrroloindole core (Scheme 1A,B), a
structural feature also found in many other biologically and
medicinally relevant compounds.1 As the capabilities of organic
chemistry grew over time and powerful new methods became
available, the synthetic strategies toward these natural products
grew more daring and at the same time more efficient.2
Aspidospermidine (2, Scheme 1A), one of the most frequent
targets, was first synthesized in 1967 by Harley-Mason3 but
continues to be a synthetic goal today, with several recent
reports.4 Ibophyllidine (3, Scheme 1B), on the other hand, was
isolated and its structure determined in 1976.5 Its first total
synthesis by Kuehne and Bohnert in 1981 made use of the
Diels−Alder reaction,6 a strategy employed several more times,
also by others.7
Following our framework reconstruction approach in the
synthesis of complex terpenoids, we now set out to expand this
rationale and, thus, developed a general access to these
structurally diverse natural products via pericyclic framework
reconstruction. Starting from a simple precursor as vinylogous
urethane 8 (Scheme 1C), we planned to construct a
bicyclo[2.2.0]hexene 6 through a sequence of a [2 + 2]-
1
structural assignment by Djerassi based on H NMR and IR
spectra as well as MS data of the natural product and its
derivatives,8 its structure was unequivocally elucidated by
single-crystal X-ray diffraction analysis of the 17-O-methyl
aspidodispermine Nb-hydrobromide.9 From the advanced key
intermediate 5, aspidodispermine (1) should be accessible via
Fischer indole reaction10 and adjustment of the oxidation state.
As an abundant and renewable starting point for this endeavor,
nicotinic acid (see the SI for details) was identified.11
Cross metathesis of 9 with allyl alcohol employing Umicore
catalyst M711 (a trifluoroacetamide-modified Hoveyda−
Grubbs second-generation catalyst) provided the [2 + 2]-
cycloaddition precursor (Scheme 2). The desired [2 + 2]-
photocyclization was then successfully performed using
acetone, both as solvent and photosensitizer,12 either in a
continuous flow setup (see the SI for details) or in batch. After
acid-mediated lactone formation (TFA), 10 was obtained in
excellent yield (75% over three steps).
For the reduction of the lactone with NaBH4, a catalytic
amount of NaOMe was crucial for a reproducible and selective
̈
photocycloaddition followed by Ramberg−Backlund contrac-
tion (8 → 7 → 6). Intermediate 6, possessing a high strain
energy, was planned to be electrocyclically rearranged to
hexadiene 5. Key pyrroloquinoline scaffold 5 could be readily
modified in its oxidation state (e.g., through the corresponding
endoperoxide and Kornblum−DeLaMare reaction to furnish
4), thus providing access to the diverse class of pyrroloquino-
line alkaloids.
Received: April 7, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01242
© XXXX American Chemical Society
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a
Scheme 1. Aspidosperma and Ibophyllidine Alkaloids
a
Chemical structure, carbon numbering, and ring system letter assignment for the Aspidosperma (A) and ibophyllidine (B) alkaloids. (C)
Retrosynthetic analysis of the Aspidosperma alkaloid aspidodispermine. [O], oxidation.
a
bicyclo[2.2.0]hexene 6 in 39% yield over two steps.
Interestingly, as an intermediate, a thiiranoxide could be
detected by MS spectrometry. Extrusion of SO, thus, was rate-
determining for this transformation. Traditionally, Ramberg−
Scheme 2. Construction of Pyrroloquinoline Scaffold 5
̈
Backlund reactions are performed with α-chloro sulfones;
however, we could not identify conditions for α-halogenation,
and direct methods (e.g., Chan or Meyers modification)16
were not successful. Yet, even when obtaining the α-chloro
sulfone by oxidation of the corresponding α-chloro sulfoxide
with mCPBA, this substrate gave 6 in a slightly lower yield
under the same reaction conditions. KOtBu was found to be a
superior base for this transformation as stronger bases (e.g.
KHMDS) or other counterions than potassium (e.g. NaOtBu)
gave much lower yields or incomplete conversion to the
intermediary thiiranoxide.
With the strained bicyclo[2.2.0]hexene 6 in hand, the formal
electrocyclic ring-opening was examined next. In their
synthesis of ladderane phospholipids, Burns described a mild
Cu+-catalyzed electrocyclic ring opening.17 When applied to
our substrate, these conditions led to no conversion, so we had
to move to classical thermal conditions.18 Indeed, heating a
diluted solution of 6 in benzene to 110 °C in a pressurized
vessel gave the desired diene 5 in a convincing yield of 82%.
Changing the solvent to toluene or lowering or raising the
reaction temperature led to less favorable results (see the SI for
details). NOE analysis on diene 5 confirmed the cis-
configuration of protons H12 and H19 (Aspidosperma
numbering).
Having the pericyclic framework reconstruction reduced to
practice, key pyrroloquinoline scaffold 5 was processed toward
aspidodispermine (1). Thus, and as depicted in Scheme 3,
reaction of 5 with singlet oxygen (1O2), generated by
photoactivation with tetraphenylporphyrin (TPP), gave the
corresponding endoperoxide. Immediate Kornblum−DeLaM-
a
See the Supporting Information for reagents and conditions. M711 =
[1,3-bis(2,6-diisopropylphenyl)-2-imidazolidinylidene]dichloro[(2-
isopropoxy)(5-trifluoroacetamido)benzylidene]ruthenium(II),
mCPBA = m-chloroperoxybenzoic acid, Ms = methanesulfonyl, py =
pyridine, TFA = trifluoroacetic acid.
reaction outcome.13 Any attempts to directly reduce the [2 +
2]-cycloaddition product (structure not shown) led to much
lower yields. Mesylation (MsCl, Et3N) then gave a dimesylate
which was transformed through the intermediacy of a thiolane
(Na2S) and subsequent oxidation with mCPBA to sulfoxide 7.
α-Chlorination with SO2Cl2 following a Pummerer mecha-
nism14 furnished an inseparable mixture of diastereomers at C4
(Aspidosperma numbering), as judged by H and 13C NMR.
1
This mixture was immediately treated with KOtBu resulting in
an atypical sulfoxide Ramberg−Backlund reaction to give
15
̈
B
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to expand this strategy further to pyrroloindole scaffolds for the
synthesis of ibophyllidine alkaloids.
Scheme 3. Completion of the Total Synthesis of
Aspidodispermine (1)
a
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01242.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Philipp Heretsch − Institute of Chemistry and Biochemistry,
̈
Freie Universitat Berlin, 14195 Berlin, Germany; orcid.org/
0000-0002-9967-3541; Email: philipp.heretsch@fu-berlin.de
Author
Franziska Reuß − Institute of Chemistry and Biochemistry, Freie
̈
Universitat Berlin, 14195 Berlin, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01242
Notes
a
See the Supporting Information for reagents and conditions. DIBAl-
The authors declare no competing financial interest.
H = diisobutylaluminum hydride, DMAP = N,N-dimethylpyridin-4-
amine, Lawesson’s reagent = 2,4-bis(4-methoxyphenyl)-1,3,2,4-
dithiadiphosphetane-2,4-disulfide, TPP = 5,10,15,20-tetraphenylpor-
phin.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the
Studienstiftung des Deutschen Volkes (Ph.D. scholarship to
F.R.). Umicore is acknowledged for a generous gift of M711
metathesis catalyst. We are grateful to Xenia Hagemann,
are reaction and subsequent acetylation in one pot furnished γ-
acetoxy enone 11. Attempts to perform the Fischer indole
reaction with phenyl hydrazine 13 (for its preparation, see the
SI) on a hydrogenated version of 11 only led to the formation
of the regioisomeric indole and none of the desired indolenine.
As we suspected interference of the lactam during the [3,3]-
sigmatropic rearrangement, we first reduced lactam 11 via a
thiolactam and subsequent desulfurization with nickel boride
to the amine 12.19 Since under these conditions the desired
hydrogenation of the enone system also occurred and Raney
nickel as well as other typically employed reagents gave
irreproducible and low yields, we settled for this result. When
performing the Fischer indole reaction on 12, the desired
indolenine was indeed the major product confirming our initial
hypothesis. Its stereoselective reduction with NaBH4 and
acetylation gave protected aspidodispermine 14.20 At this
point, the stereoconfiguration of the 5-acetoxy group could be
verified through its unusual upfield shift (1.36 ppm), hinting at
the acetoxy methyl to be orthogonally oriented toward the
aromatic ring. The total synthesis of aspidodispermine (1) was
then completed through selective deacetylation (DIBAl-H)
and hydrogenolysis of the benzyl ether. Reported spectroscopic
data (see the SI) were in agreement with our synthetic material
and recorded 2D NMR spectra further corroborated Djerassi’s
proposed structure.8
̈
Mykhaylo Alekseychuk, and Merlin Kleoff (Freie Universitat
Berlin) for experimental assistance. The Core Facility
BioSupraMol supported by the DFG is acknowledged.
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