Total Synthesis of Naphterpin and Marinone Natural Products

Article abstract of DOI:10.1021/acs.orglett.9b03095

A concise and divergent strategy for the synthesis of the naphterpin and marinone meroterpenoid families has been developed. The approach features a succession of pericyclic reactions-an aromatic Claisen rearrangement, a retro-6?€-electrocyclization, and

Full text of DOI:10.1021/acs.orglett.9b03095

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Total Synthesis of Naphterpin and Marinone Natural Products
Lauren A. M. Murray, Thomas Fallon, Christopher J. Sumby, and Jonathan H. George*
Department of Chemistry, University of Adelaide, Adelaide, South Australia 5005, Australia
S
* Supporting Information
ABSTRACT: A concise and divergent strategy for the synthesis
of the naphterpin and marinone meroterpenoid families has
been developed. The approach features a succession of
pericyclic reactionsan aromatic Claisen rearrangement, a
retro-6π-electrocyclization, and two Diels−Alder reactions
which facilitated the first total synthesis of naphterpin itself in
five steps from 2,5-dimethoxyphenol, alongside similar syntheses of 7-demethylnaphterpin and debromomarinone. Late-stage
oxidation and bromination reactions were also investigated, leading to the first total syntheses of naphterpins B and C and
isomarinone.
arine and terrestrial strains of Streptomyces bacteria have
(7) and marinone (8) were isolated by Fenical and coworkers
from an actinomycete derived from marine sediment in 1992,6
with isomarinone (9) reported in 2000.7
M
been an excellent source of new natural products with
novel structures and potent bioactivity,1 including naphtho-
quinone meroterpenoids such as the naphterpins (Figure 1a),
Previous 13C labeling studies by Seto et al.8 and Moore et
al.9 have indicated that the naphterpins and marinones are
biosynthetically derived from 1,3,6,8-tetrahydroxynaphthalene
(THN, 10) and either geranyl or farnesyl diphosphate,
respectively, although the precise biosynthesis was not
immediately obvious (Scheme 1). We recently proposed a
Scheme 1. Proposed Biosynthesis and Previous Biomimetic
Synthesis of the Naphterpins and Marinones
Figure 1. THN meroterpenoids of interest in this work: (a) the
naphterpins, (b) the naphthgeranines, (c) the marinones.
biosynthetic pathway to the naphterpins and marinones in
which the THN ring system undergoes oxidation via “cryptic
chlorination” catalyzed by vanadium-dependent haloperox-
idases (VHPOs), despite the absence of chlorine in these
natural products.10 This biosynthetic speculation was originally
based on analogies to the merochlorin11 and napyradiomycin12
families of marine Streptomyces meroterpenoids, which we have
previously shown to be biosynthesized via the VHPO-catalyzed
dearomatization of THN derivatives. On the basis of our
the naphthgeranines (Figure 1b), and the marinones (Figure
1c). Naphterpin (1) was the first natural product discovered in
this family, isolated by Seto et al. in 1990 from Streptomyces sp.
CL-190 that was collected in Ishigaki Island, Okinawa.2 The
isolation of the oxidized derivatives naphterpin B (2) and
naphterpin C (3) from the same microbial source was reported
later in 2005.3 Naphthgeranine A (4, also independently
reported as 7-demethylnaphterpin4) was isolated alongside
several oxidized derivatives such as naphthgeranine B (5) and
naphthgeranine C (6) by Zeeck in 1991.5 Debromomarinone
Received: August 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03095
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
biosynthetic studies, we achieved a biomimetic synthesis of 7-
demethylnaphterpin (4) and debromomarinone (7) from the
protected THN derivative 11.10 We also synthesized several
proposed biosynthetic intermediates, which were used to
decipher the reactivity of two VHPO enzymes from the
putative marinone gene cluster that chlorinate and dearomatize
prenylated THN derivatives. However, because of the
complexity of the biosynthetic pathway, our biomimetic
route to 7-demethylnaphterpin (4) and debromomarinone
(7) was 15 steps from commercially available (3,5-
dimethoxyphenyl)acetic acid (Scheme 1). The biomimetic
strategy was too long and too linear to allow the synthesis of
further oxidized or brominated members of the naphterpin/
marinone family.
hydroquinone). Heating 12a with MgBr2 in MeCN induced a
retro-6π-electrocyclization and alkene isomerization to give a
reactive enone, which then underwent an intramolecular
Diels−Alder reaction to form naphterpin (1). The labile C-8
methyl ether was also cleaved under these mild conditions.
The epoxidation of naphterpin with m-CPBA gave a separable
3:1 mixture of epoxides 19 and 20. Unexpectedly, the major
epoxide diastereomer 19 results from the electrophilic attack
on the concave face of the Δ12,13 alkene of 1. However, Brase et
al. observed a similar ratio of endo and exo epoxide products in
the epoxidation of a related meroterpenoid system.22 The
relative configuration of 19 was unambiguously assigned via
single-crystal X-ray crystallography, whereas 20 was assigned
using nuclear Overhauser effect (NOE) data and a comparison
23
3
We have therefore devised a simpler, nonbiomimetic
retrosynthetic analysis of the naphterpins that is not con-
strained by the use of a THN building block (Scheme 2). We
of key J coupling constants with computational predictions.
The ring opening of epoxides 19 and 20 with lithium
diisopropylamide (LDA) then gave naphterpin B (2) and
naphterpin C (3), respectively, presumably by an E1cB
mechanism that involves an intermediate o-quinone methide
enolate, with the retention of the stereochemistry at C-13. The
relative configuration of naphterpin C was originally assigned
by Seto via a rotating frame Overhauser enhancement
spectroscopy (ROESY) correlation between Me-20 and Me-
18. Replacing diene 13a with 13b24 in the intermolecular
Diels−Alder reaction with quinone 14 allowed the synthesis of
12b, followed by 7-demethylnaphterpin (4) upon Lewis-acid-
catalyzed rearrangement. To date, we have been unable to
convert 4 into more oxidized members of the naphthgeranine
family, such as naphthgeranines B and C (5 and 6), via allylic
oxidations.
Scheme 2. Retrosynthetic Analysis of the Naphterpins
The synthetic strategy was also applicable to the marinone
family by replacing the prenyl propargylic carbonate 16 with
geranyl propargylic carbonate 21,25 which was coupled to 15
to give 22 (Scheme 4). The thermal aromatic Claisen
rearrangement of 22, followed by oxidation gave quinone 23,
which underwent a facile intermolecular Diels−Alder reaction
with 13b to give naphthoquinone 24. The conversion of 24 to
debromomarinone (7) was then achieved via the now familiar
MgBr2-catalyzed cascade of retro-6π-electrocyclization and the
intramolecular hetero-Diels−Alder reaction. Finally, debromo-
marinone was brominated using 1.5 equiv N-bromosuccini-
mide (NBS) in CH2Cl2 at 0 °C. Under these conditions, we
observed the exclusive bromination of 7 at C-7 to give
isomarinone (9) in 38% isolated yield. We observed no
bromination at C-5 and therefore no formation of marinone
(8). Heteronuclear multiple bond correlation (HMBC)
correlations confirmed the original assignment of the
isomarinone bromination pattern. In nature, the selective
bromination of 7 at C-5 to give marinone (8) might occur
under the control of a vanadium-dependent haloperoxidase
enzyme, or it could occur at an earlier point in the biosynthetic
pathway.
envisaged that the cis-fused cyclohexane and pyran rings of 1
and 4 could be formed by an intramolecular hetero-Diels−
Alder reaction of a reactive enone, which is unveiled via a late-
stage retro-6π-electrocyclization (and alkene isomerization) of
naphthoquinones 12a/b. This endgame was also used in our
previous synthesis.10 However, the disconnection of 12a/b
from the simple Brassard dienes13 13a/b and quinone 14 via
an intermolecular Diels−Alder reaction14 (and aerobic
oxidation) had the potential to significantly shorten our
previous biomimetic synthesis and therefore allow divergent
access to oxidized and brominated family members. A related
intermolecular Diels−Alder reaction was used in Nakata’s total
synthesis of the napyradiomycin A80915G12a and also in
Tapia’s synthetic study toward the naphterpins (but no
naphterpin total syntheses were achieved by this route).15
As shown in Scheme 3, our synthesis of the naphterpin
family began with the commercially available 2,5-dimethox-
yphenol (15),16 which was coupled to propargylic carbonate
1617 in the presence of DBU and copper(II) chloride18 to give
17. The thermal rearrangement of 17 gave chromene 18 in
high yield via a sequence of aromatic Claisen rearrangement to
give an o-allenyl phenol, followed by a 1,5-hydrogen shift to
give an o-quinone methide and a final oxa-6π-electrocycliza-
tion.19 Chromene 18 was then oxidized to give quinone 14
using PhI(O2CCF3)2.20 A regioselective intermolecular Diels−
Alder reaction between 14 and diene 13a21 proceeded
spontaneously at room temperature to give naphthoquinone
12a (presumably via the aerobic oxidation of an intermediate
While searching online databases for further members of the
naphterpin family of meroterpenoids, we found a report of
“naphthoquinone C” (25), isolated from a marine-derived
Penicillium sp. (Figure 2).26 Given the likely biosynthetic origin
of 25 from THN and geranyl diphosphate, we thought that its
structure was probably misassigned. Indeed, the comparison of
1
the H NMR spectrum of 25 recorded in CD3OD showed an
excellent match with the corresponding data for the previously
reported naphthgeranine C (6).5a,27 Unfortunately, the 13C
NMR spectra of the two natural products were recorded in
different solvents; nevertheless, we suggest that naphthoqui-
B
DOI: 10.1021/acs.orglett.9b03095
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Organic Letters
Letter
Scheme 3. Divergent Total Synthesis of Naphterpin, Naphterpin B, Naphterpin C, and 7-Demethylnaphterpin
Scheme 4. Total Synthesis of Debromomarinone and
Isomarinone
Figure 2. Suggested structure revision of naphthoquinone C.
structures 6 and 25 and the comparison to the natural product
data.23
In conclusion, we have developed a concise, modular
strategy for the synthesis of the naphterpin and marinone
families of marine merotepenoids. This has resulted in the
divergent synthesis of six natural products, with naphterpin,
naphterpin B, naphterpin C, and isomarinone all synthesized
for the first time. The synthetic strategy features a sigmatropic
rearrangement, an electrocyclization and two Diels−Alder
reactions, thus showcasing the power of pericyclic reactions in
the construction of complex natural products.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03095.
none C has been incorrectly assigned, and that it is probably
reisolated naphthgeranine C.28 This proposal is supported by
the computational prediction of the 13C NMR spectra of
Experimental procedures and analytical data for all new
compounds (PDF)
C
DOI: 10.1021/acs.orglett.9b03095
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
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CCDC 1944007 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, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jonathan.george@adelaide.edu.au.
ORCID
Christopher J. Sumby: 0000-0002-9713-9599
Jonathan H. George: 0000-0002-7330-2160
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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D
DOI: 10.1021/acs.orglett.9b03095
Org. Lett. XXXX, XXX, XXX−XXX