Synthesis of Two Key Fragments of the Complex Polyhalogenated Marine Meroterpenoid Azamerone

Article abstract of DOI:10.1021/acs.orglett.9b00090

A concise route toward two advanced fragments in the context of the total synthesis of the unique natural product azamerone is reported. Key synthetic features include the enantioselective synthesis of an epoxysilane and its Lewis-acid-induced cyclization and the installation of the pyridazine ring via a formylation/condensation sequence. This route provides strategic insights into the chemistry of phthalazinediols, facilitating synthetic approaches toward this class of natural products.

Full text of DOI:10.1021/acs.orglett.9b00090

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Two Key Fragments of the Complex Polyhalogenated
Marine Meroterpenoid Azamerone
Simon D. Schnell, Anthony Linden, and Karl Gademann*
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
S
* Supporting Information
ABSTRACT: A concise route toward two advanced frag-
ments in the context of the total synthesis of the unique
natural product azamerone is reported. Key synthetic features
include the enantioselective synthesis of an epoxysilane and its
Lewis-acid-induced cyclization and the installation of the
pyridazine ring via a formylation/condensation sequence. This
route provides strategic insights into the chemistry of
phthalazinediols, facilitating synthetic approaches toward this
class of natural products.
ver the years, marine-sediment-derived bacteria of the
order of Actinomycetales (actinomycetes) have been
Scheme 1. Biosynthesis and Retrosynthetic Analysis
O
recognized as a valuable source for the discovery of novel,
structurally unique natural products with interesting biological
activity,1,2 such as antibacterial,2 anticancer,3 and anti-infective4
properties. As an example of this chemical diversity, these
organisms produce a family of halogenated natural products
called napyradiomycins, of which there are more than 40 known
members.5 Surprisingly, only the total synthesis of one member
of this class, namely, napyradiomycin A1, has been reported,6
and very recently, Moore and co-workers published the total
enzyme synthesis of napyradiomycins A1 and B1.7 In 2006,
Fenical and co-workers isolated a new member of this class that
could be identified as the unusual meroterpenoid phthalazinone
azamerone (1).8 In addition to pyridazomycin, azamerone (1)
constitutes the only natural product containing a pyridazine ring,
making it a very interesting target for total synthesis within this
family of natural products.9 In contrast to the biosynthesis of
pyridazomycin,9 in which the N−N bond has been suggested to
be formed through the cyclization of L-ornithine, Moore’s group
could provide evidence that this is not the case for azamerone
(1).10 Isolation of co-produced polyhalogenated meroterpe-
noids and analogues containing a diazo functionality (2 and 3)
strongly suggests that the N−N bond in azamerone (1) is
formed via an oxidative rearrangement of the diazo functionality
of compound 3.10 This could be verified by 15N and 13C labeling
studies.10
In the context of our interest in N−N bond containing natural
products,11 the structurally unique phthalazinone core of
azamerone (1), the interesting halogenation pattern, and the
highly functionalized cyclohexane side chain, we selected this
unique natural product as a challenging target for total synthesis.
Our retrosynthesis of azamerone (1) aimed at disconnecting
the bond between the cyclohexane unit 4 and the tricyclic
phthalazinedione 5, which we envisioned to install at a late stage
via a metal-mediated C−C bond-forming reaction (Scheme 1).
Interestingly, Burns and co-workers recently and independently
disclosed a similar strategy by employing a cyclic boronic
hemiester and an azoquinone, which successfully led to the total
synthesis of azamerone (1).12 The acetyl side chain of
azamerone (1) would be installed via a protecting-group-
directed, regioselective lithiation of the pyridazine ring of
tricycle 6, followed by trapping with aldehyde, to produce
tricyclic structure 5. The pyridazine ring, in turn, would be
formed by a double formylation followed by a condensation,
which leads to bicycle 7 as a suitable starting material for our
synthetic endeavors.
Our synthesis of key bicyclic hydroquinone 7 (Scheme 2)
started with a three-step sequence,13 which delivered protected
intermediate 8 in high yield from commercially available 2,5-
dimethoxybenzaldehyde (9). Unfortunately, deprotection of the
Received: January 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00090
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
followed by an electrophile (MOMBr, MEMCl, Me3OBF4),
dearomatization was observed, leading to the sole isolation of
dearomatized, nitrogen-protected compounds of the general
structure 15 in up to 50% yield on a 10 mg scale. The structure
was confirmed by X-ray analysis of the MOM-protected tricycle
16 (Scheme 2). Increasing the scale to 50 mg resulted in a drastic
decrease in yield, and additionally, migration of the TIPS group
could be observed in trace amounts.
Scheme 2. Synthesis of the Core Structure of Azamerone (1)
In parallel, we turned our attention to the enantioselective
synthesis of the cyclohexane unit of azamerone (1). Previously,
Snyder and co-workers developed a chloronium-induced
cyclization method for the synthesis of a precursor of the
cyclohexane unit.18,19 However, this reaction delivered only
racemic material, rendering a tedious separation via resolution
mandatory.18 Thus, our first approach sought to employ the
enantioselective, catalytic diborylation−double allylation strat-
egy developed by the group of Morken.20
To explore the feasibility of this approach, we synthesized
diene 17 in three steps from phosphorus ylide 18.21 Wittig
olefination with acrolein furnished diene 19, which could be
reduced to primary alcohol 20 using DIBAL-H.21 Protection of
the primary hydroxy group with tert-butyl(chloro)-
diphenylsilane then furnished silyl ether 17. Oxidation of 5-
hydroxy-2-pentanone (21) using (diacetoxyiodo)benzene and
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl afforded dicarbonyl
22.20 We then turned our attention to the key tandem
diborylation−double allylation reaction. Gratifyingly, the
enantioselective Pt-catalyzed diboration of diene 17 with
bis(pinacolato)diboron (B2pin2) using Pt(dba)3 as a catalyst
and a TADDOL-derived ligand, followed by in situ trapping of
the diborylated species with dicarbonyl 22, delivered cyclo-
hexane 23 in 60% yield with a dr of 9:1 (as judged by 1H NMR at
position C1) (Scheme 3) and 88% ee. The relative configuration
methyl groups under standard conditions (BBr3, BCl3, AlCl3)
led only to decomposition.14
However, oxidative demethylation using [bis-
(trifluoroacetoxy)iodo]benzene (PIFA) in acetonitrile/water
(2:1, v/v) afforded the corresponding para-quinone in good
yield.15 Subsequent reduction using in situ generated sodium
triacetoxyborohydride afforded hydroquinone 7 in 89% yield.
With this intermediate in hand, we set out to investigate the key
three-step sequence for installing the pyridazine ring of the
natural product. Upon treatment of hydroquinone 7 with
piperidine and aqueous formaldehyde solution, the desired
diaminoalkylation was observed, delivering compound 10 in
75% yield.16 The reaction of 10 in acetic acid with a solution of
chromium(VI) oxide in acetic acid/water (1:1, v/v) furnished
the desired diformyl dihydroquinone 11.17 Ring closure was
then affected by condensation with hydrazine hydrate, which led
to pyridazine core structure 12 in 88% yield. However, tricycle
12 proved to be prone to oxidation, which leads to the formation
of quinone 13 in trace amounts upon column chromatography.
Full conversion to intermediate 13 was observed after 20 h
under an oxygen atmosphere.
Scheme 3. Tandem Diborylation−Double Allylation
With these promising results in hand, we set out to investigate
the introduction of the acetyl side chain. Regioselective
protection of the hydroxy group at position C-10 of tricycle
12 proved to be challenging due to decomposition of the
product in the reaction mixture. After extensive experimenta-
tion, suitable conditions were identified, which involved a large
excess (10 equiv) of triisopropylsilyl chloride (TIPSCl) and 4-
(dimethylamino)pyridine (DMAP) as a catalyst and base, which
furnished the desired regioisomer 14, as unambiguously shown
by X-ray crystallography, in 74% yield.
was validated by deprotection of the silyl ether by using TBAF to
afford triol 24, from which a suitable crystal for an X-ray crystal
structure determination could be obtained. With these results,
we set out to explore the deoxygenation of the primary hydroxy
group. However, even after employing a large variety of
conditions, this was not successful. Instead of the formation of
the desired compound 25, the main byproducts observed
included oxetane formation (I2, PPh3, imH) or thiocarbonate
However, when treating the mono-TIPS-protected hydro-
quinone 14 with a base (NEt3, NaH, LiHMDS, K2CO3)
B
DOI: 10.1021/acs.orglett.9b00090
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
formation (TCDI, NEt3, DMAP) when trying to install a
thiocarbonylimidazole precursor for radical deoxygenation. On
the basis of these results, we decided to focus on a different
strategy, which utilizes the Lewis-acid-induced cyclization of
epoxysilanes (Scheme 4).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: karl.gademann@chem.uzh.ch.
ORCID
Anthony Linden: 0000-0002-9343-9180
Karl Gademann: 0000-0003-3053-0689
Notes
Scheme 4. Enantioselective Synthesis of the Cyclohexane
Unit
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Angela Amsler and Andrea Turrin (UZH) for
laboratory assistance.
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