Biomimetic synthesis of (±)-merochlorin B

Article abstract of DOI:10.1021/ol500800z

A short total synthesis, guided by biosynthetic considerations, of racemic merochlorin B is presented. The formation of its isomer, merochlorin A, was not observed under the conditions. Key steps include a directed ortho-metalation (DoM), a selective demethylation, an ortho-allylation, and an oxidative [3 + 2]-cycloaddition mediated by an iodine(III) reagent.

Full text of DOI:10.1021/ol500800z

Letter
pubs.acs.org/OrgLett
Biomimetic Synthesis of ( )-Merochlorin B
Robin Meier, Sebastian Strych, and Dirk Trauner*
Department of Chemistry and Center for Integrated Protein Science, University of Munich (LMU), Butenandtstraße 5-13,
81377 Munchen, Germany
̈
S
* Supporting Information
ABSTRACT: A short total synthesis, guided by biosynthetic considerations, of racemic merochlorin B is presented. The formation
of its isomer, merochlorin A, was not observed under the conditions. Key steps include a directed ortho-metalation (DoM), a
selective demethylation, an ortho-allylation, and an oxidative [3 + 2]-cycloaddition mediated by an iodine(III) reagent.
he merochlorins, 1−4, are a small family of meroterpenoids
incorporates a heterocycle, a chlorinated vinylogous ester, and,
Trecently isolated from the sediment bacterium Streptomyces like merochlorin A, 1, a propan-2-ylidenecyclopentane. Fur-
spectrabilis strain CNH 189 (Figure 1).1 Merochlorins A, 1, and
thermore, 2 features three contiguous stereocenters, one of which
is quaternary.
B, 2, have attracted considerable attention due to their unusual
structures and their high activity against methicillin-resistant
strains of Staphylococcus aureus.1
Biosynthetically, all members of the merochlorin family have
been proposed to derive from a common chlorinated tetra-
hydroxynaphthalene (THN) derivative 5 (Scheme 1).1,2 Moore
and co-workers identified the biosynthetic gene cluster associated
with 5 and proposed that a THN synthase, a polyprenyl synthase, a
prenyltransferase, and a vanadium-dependent haloperoxidase are
involved in its formation.1b Its subsequent cyclization to merochlorin
A, 1, and B, 2, would proceed via epoxidation or chlorination of the
central double bond.
This proposal was modified by George and co-workers who
recently disclosed a biomimetic synthesis of merochlorin A, 1.2
They assumed that oxidation of the electron-rich aromatic core
of 5, possibly by an enzyme that contains an iron−sulfur cluster,
would give rise to phenoxonium ion 6. This reactive intermediate
would then cyclize to merochlorin A, 1, or B, 2, via a [5 + 2]- or
[3 + 2]-cycloaddition depending on the orientation of the terpenoid
side chain (Scheme 1).
We now report the total synthesis of ( )-merochlorin B, 2, that
was guided by similar biosynthetic considerations. Interestingly,
the formation of merochlorin A, 1, was not observed under our
conditions, whereas George and co-workers did not observe the
Figure 1. Merochlorins A−D, 1−4, isolated from Streptomyces
spectrabilis strain CNH-189.
Merochlorin A, 1, features a tetracarbocyclic ring system
with four contiguous stereocenters, two of which are quaternary.
Its isomer, merochlorin B, 2, possesses a ring system that
Received: March 17, 2014
Published: May 7, 2014
© 2014 American Chemical Society
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Scheme 1. Presumed Biosynthetic Origin of Merochlorin A, 1,
and B, 22
Scheme 3. Synthesis of the Naphthalene Building Blocks 15
and 16 and of Allylic Bromide 19
formation of merochlorin B, 2, under theirs. As such, our work
provides another example for a subtle variation of a substrate that
results in a markedly different outcome of a cascade reaction.
Retrosynthetically, we envisioned that 1 and 2 could be
obtained from naphthalene 8, which is a protected version of 5
(Scheme 2).3 Compound 8 could be accessed by a late stage
necessary at this point to achieve the protection of the sterically
more hindered hydroxyl group in the peri-position of the
naphthalene core 12.
Scheme 2. Retrosynthetic Analysis of Merochlorins A, 1, and
B, 2
The ability of methoxy groups to direct the metalation of
aromatic systems is well described in the literature.7 In our case,
the cooperative interaction of the two methoxy groups led to a
completely regioselective metalation. Treatment of naphthalene
13 or 14 with n-BuLi and TMEDA formed the corresponding
lithiated species, which was quenched with hexachloroethane
(C2Cl6) to form the chlorinated naphthalene cores 15 and 16,
respectively, in high yield. The advantages of C2Cl6 over other
Cl+-sources have been documented in the literature.8
Initial experiments to access the terpenoid side chain using a
Horner−Wadsworth−Emmons strategy9 did not lead to accept-
able results in our case. We therefore took recourse to a Peterson
olefination10 starting from commercially available silyl acetate 17
which was alkylated with geranyl bromide, 10, in good yield
(Scheme 3).11 Subsequent treatment with LDA followed by the
addition of acetone gave α,β-unsaturated ester 18.12 Reduction
followed by Appel reaction then provided the sensitive bromide
19 in good yield.
With compounds 15, 16, and 19 in hand we investigated the
formation of cyclization precursor 21 (Scheme 4). Our initial
plan was to incorporate the side chain by a second directed ortho-
metalation of the aromatic core 15 followed by reaction of the
resulting organolithium compound 20 with the bromide 19.13
Although the regioselective formation of 20 could be proven by
D2O quench, it was impossible to connect side chain 19 in that
manner. The transmetalation of 20 with various metals (Cu, Mg,
Zn, SnMe3) and addition of 19 with and without palladium
catalysis did not lead to the desired coupling product 21
either. As a consequence, we changed the order of events and
allylation with a terpenoid side chain ultimately derived from
commercially available geranyl bromide, 10. Furthermore, the
incorporation of the chlorine atom could be achieved by
a directed ortho-metalation (DoM) of a protected dimethoxy-
naphthalene derivative which in turn could be accessed via
Dieckmann condensation starting from phenylacetic acid methyl
ester 9.
Accordingly, our synthesis commenced with the preparation of
6,8-dihydroxy-1,3-dimethoxynaphthalene, 12, from phenylacetic
acid 9 using a modification of a known procedure (Scheme 3).4
Friedel−Crafts acylation of 9 then afforded acetophenone 11
which underwent Dieckmann cyclization in excellent yield upon
treatment with sodium hydride.5,6 Protection of both phenolic
hydroxyl groups with TBS or TIPS triflate afforded naphthalenes
13 and 14. The use of the more reactive triflate reagents was
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Scheme 4. Synthesis of Cyclization Precursor 23
Scheme 5. Synthesis of Merochlorin B, 2
derivative 26, which still contained one of the two silyl ethers
of the starting material (Scheme 5). Subsequent deprotection
afforded merochlorin B, 2, as a single diastereomer and in 30%
overall yield from 23. The spectral data of our synthetic compound
are in accordance with those reported by Moore et al.,1b and Prof.
Moore agrees with this analysis (see Supporting Information).21
Interestingly, we did not observe the formation of merochlorin
A, 1, under our oxidative conditions. We believe that this is not
due to a variation in the oxidant but rather due to the presence
of a methyl ether in intermediate 25. In the case of George’s
merochlorin A, 1, synthesis,2 the corresponding cyclization
precursor bears a free hydroxyl group at the C-1 position, which
can be deprotonated, rendering the resultant enolate highly
nucleophilic. Presumably, the methyl substituent in intermediate
25 increases the relative nucleophilicity of the carbonyl, thus
favoring the [3 + 2]-pathway. The resulting oxocarbenium ion is
either directly demethylated by nucleophilic attack or forms a
labile acetal that is lost upon aqueous workup.
In conclusion, we have achieved the first total synthesis of
( )-merochlorin B, 2, a biologically active chlorinated meroterpe-
noid, by a longest linear sequence of eight steps starting from
commercially available phenylacetic acid methyl ester 9. Key steps
include a directed ortho-metalation (DoM), a chemoselective
demethylation of a naphthalene, and a biosynthetically inspired
oxidative [3 + 2]-cycloaddition using an iodine(III) reagent
generated in situ. Attempts to achieve asymmetric syntheses of the
merochlorins are currently underway in our laboratories and will be
reported in due course.
investigated demethylation of the chlorinated naphthalenes 15
and 16. After extensive optimization, compound 16 could be
selectively deprotected by boron tribromide in good yield. The
addition of proton sponge and use of the TIPS protected core 16
was found to be essential for a fast and clean conversion to naphthol
22 in the presence of silyl protecting groups.14 Importantly, double
demethylation was not observed under these conditions.
Gratifyingly, naphthol 22 underwent clean ortho-allylation by
treatment with sodium hydride and subsequent trapping with
allylic bromide 19.15 The resulting prenylated naphthol 23 was
obtained in good yield as an inseparable 4:1 mixture of isomers,
presumably due to an isomerization at the double bond indicated
in Scheme 4. An analogous isomerization was observed by
George and co-workers in their synthesis of merochlorin A, 1.2
In an attempt to synthesize both merochlorin A, 1, and B, 2, we
treated 23 with lead(IV) tetraacetate (LTA). These conditions,
also used by George and co-workers,2 resulted in a complex
mixture of products. Based on 1H NMR and mass spectroscopy
data, we determined that the major component of this mixture
resulted from Wessely oxidation (not shown).16 A much cleaner
reaction was observed by changing the oxidant to lead(IV) tetra-
benzoate, which can be prepared from LTA via ligand exchange,17
and use of a mixture of dichloromethane and trifluoroethanol
(TFE) as a solvent (Scheme 5). Under these conditions, the
Wessely oxidation product 24 could be isolated in moderate yield.
Inspired by the work of Horne et al.,3d we tried to use 24 as a
precursor of the requisite phenoxonium ion. However, when 24
was treated with a variety of Brønsted and Lewis acids, no [5 + 2]-
or [3 + 2]-cycloaddition products could be observed.
ASSOCIATED CONTENT
* Supporting Information
We next turned to iodine(III) reagents18 as oxidants. After
extensive screening, we found that a variant of Koser’s reagent
[PhI(OH)OTs],19 generated in situ, gave a desired product. Mixing
iodosobenzene (PhIO) with trifluoromethanesulfonic acid,20
followed by addition to naphthol 23, afforded merochlorin B
■
S
Experimental details as well as spectroscopic and analytical data
for all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
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(b) Tanaka, T.; Kumamoto, T.; Ishikawa, T. Tetrahedron Lett. 2000, 41,
10229. (c) Yamaguchi, S.; Kobayashi, M.; Harada, S.; Miyazawa, M.;
Hirai, Y. Bull. Chem. Soc. Jpn. 2008, 81, 863.
AUTHOR INFORMATION
■
Corresponding Author
(15) (a) Yamada, S.; Takeshita, T.; Tanaka, J. Bull. Chem. Soc. Jpn.
1986, 59, 2901. (b) Hoarau, C.; Pettus, T. R. R. Synlett 2003, 1, 127.
(c) Le Noble, W. J. Synthesis 1970, 1, 1. (d) Kornblum, N.; Lurie, A. P. J.
Am. Chem. Soc. 1959, 81, 2705. (e) Bates, R. W.; Gabel, C. J. Tetrahedron
Lett. 1993, 34, 3547.
*E-mail: dirk.trauner@lmu.de.
Notes
The authors declare no competing financial interest.
(16) (a) Wessely, F.; Lauterbach-Keil, G.; Sinwel, F. Monatsh. Chem.
1950, 81, 811. (b) Wessely, F.; Sinwel, F. Monatsh. Chem. 1950, 81,
1055.
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(b) Buston, J. E. H.; Howell, H. J.; Moloney, M. G.; Manson, V. C.;
Thompson, R. M. Main Group Met. Chem. 1998, 21, 51.
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dearomatization reactions, see the following and references therein:
ACKNOWLEDGMENTS
■
Financial support by the Deutsche Forschungsgemeinschaft
(SFB 749) is acknowledged. Additionally, the authors would like
to acknowledge Dr. Tatsuya Urushima (LMU, Munchen) for
̈
helpful discussions and experimental assistance.
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