Total Syntheses of FR-901235, Auxarthrones A-D, and Lamellicolic Anhydride

Article abstract of DOI:10.1021/acs.orglett.0c03401

In our previous study, an unusual rearrangement reaction was discovered whereby dinaphthyl ketones with three hydroxy groups at restricted positions were transformed into a phenalenone ring and a benzene ring. Using the rearrangement as a key reaction, the first total syntheses of FR-901235 and auxarthrones A-D from an unstable triketone common intermediate are described. Furthermore, lamellicolic anhydride was synthesized from the triketone. This conversion is part of the putative biosynthetic pathway and was achieved experimentally for the first time.

Full text of DOI:10.1021/acs.orglett.0c03401

pubs.acs.org/OrgLett
Letter
Total Syntheses of FR-901235, Auxarthrones A−D, and Lamellicolic
Anhydride
Kotaro Kiyotaki, Takuto Kayukawa, Ayumi Imayoshi, and Kazunori Tsubaki*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03401
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: In our previous study, an unusual rearrangement reaction
was discovered whereby dinaphthyl ketones with three hydroxy groups at
restricted positions were transformed into a phenalenone ring and a
benzene ring. Using the rearrangement as a key reaction, the first total
syntheses of FR-901235 and auxarthrones A−D from an unstable
triketone common intermediate are described. Furthermore, lamellicolic
anhydride was synthesized from the triketone. This conversion is part of
the putative biosynthetic pathway and was achieved experimentally for
the first time.
dehydration between the inner two hydroxy groups usually took
place to give the corresponding dibenzoxanthone.2 Although, in
the case of 1, treatment with acid selectively led to phenalenone
2 in 84% yield. This rearrangement is a unique reaction in which
a compound composed of two naphthalene rings is converted
into a phenalenone ring and a benzene ring by aromatic ring
recombination. In addition, this transformation is a new
synthetic route for the construction of the phenalenone
skeletons. After precise experiments, we discovered that the
presence of the three hydroxy groups shown in red in compound
1 in Figure 1A are essential for the rearrangement reaction to
proceed.
uring the development of xanthone-type fluorescent dyes,
Dwe discovered an unusual rearrangement reaction (Figure
1A).1 Thus, when a dinaphthyl ketone possessing hydroxy
groups at certain positions was treated with acid or base, a
Compound FR-901235 (3) was isolated from a culture of
Paecilomyces carneus F-4882 as an immunomodulator in 1989.3
Auxarthrones A−E (4−8)4 were isolated from a culture of
Auxarthron pseudauxarthron in 2017. Among these compounds,
the structure of auxarthrone E (8) has not been precisely
determined by NMR spectra and is a proposed structure based
on the MS and UV spectra obtained from the LC-MS isolation
step. Antifungal activity has been reported for auxarthrone A
(4).4 Lamellicolic anhydride (9) was isolated from Verticillium
lamellicola in 1973 and had weak antibacterial and antifungal
activity.5 Despite their curious phenalenone backbone and
Received: October 12, 2020
Figure 1. (A) Unexpected framework rearrangement reaction. (B)
Structures of FR-901235 (3), auxarthrones A−E (4−8), and
lamellicolic anhydride (9).
https://dx.doi.org/10.1021/acs.orglett.0c03401
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
functions,6 the total syntheses of these compounds have not
been reported (Figure 1B).
groups for the rearrangement reaction. Finally, compound 12
could be prepared by a coupling between two naphthalene units
13 and 14.
The synthetic route for penta-substituted naphthalene 13 is
shown in Scheme 1A. 1,8-Naphthalic anhydride (15) was
The proposed biosynthetic pathway of these phenalene
compounds is shown in Figure 2.7 In a microorganism, the
Scheme 1. Synthesis of the Naphthalene Units 13 and 14: (A)
Synthetic Route for 13 Using Lossen Rearrangement and (B)
Synthetic Route for Trisubstituted Naphthalene 14
Figure 2. Proposed biosynthesis of compounds 3−9 through common
intermediate triketone 10.
heptaketide precursor is condensed to construct a phenalenone
ring, which is then oxidized to afford triketone derivative 10. An
intermolecular aldol reaction proceeds between the resulting
triketone 10 and a ketonic molecule, which is used as a solvent in
the isolation steps from the culture to afford FR-901235 (3) and
auxarthrones A (4), B (5), and D (7). Finally, intramolecular
aldol condensation occurs to generate auxarthrone C (6) and
auxarthrone E (8) from 5 and 7, respectively. Because the
intermolecular aldol reactions are non-enzymatic processes,
these compounds are isolation artifacts and the asymmetric
carbons in these compounds would be racemic. Lamellicolic
anhydride (9) is a further oxidized compound of 10, and several
natural compounds downstream from 9 have also been
reported.8 In this study, we will describe the first and
comprehensive syntheses of FR-901235 (3), auxarthrones A−
D (4−7), and lamellicolic anhydride (9) using the novel
rearrangement reaction as the key reaction.
A retrosynthetic analysis of these compounds is shown in
Figure 3. FR-901235 (3) and the auxarthrones 4−8 could be
prepared through an aldol reaction between triketone 109 and
an appropriate ketone. Triketone 10 would be constructed by
oxidative removal of the side chain of phenalenone 11 followed
by further oxidation. Phenalenone 11 could derive from
dinaphthyl ketone 12, which has the three necessary hydroxy
selected as a starting material as it is readily available and has a
symmetrical structure. First, compound 15 was brominated with
2.5 equiv of NBS. Although bromination at the meta positions of
each carbonyl group predominated, the reaction was not
completely selective, and brominated compounds at the para
positions were also generated as byproducts. Due to the low
solubility of these compounds, it was difficult to separate them
by column chromatography. Therefore, the resulting reaction
mixture was directly treated with n-butylamine in order to
convert it into the more soluble imide 16. Fortunately,
byproducts with bromine at the para position showed high
reactivity for ipso substitution with n-butylamine. As a result,
these byproducts and desired compound 16 had different
polarities and were easily separated by column chromatography,
thus enabling access to compound 16 in 37% yield. Then, the
two bromine atoms of 16 were displaced to the corresponding
boronic acid pinacol ester (Bpin) using the Miyaura borylation
reaction followed by oxidation with hydrogen peroxide.
Figure 3. Retrosynthetic analysis of FR-901235 (3) and auxarthrones
A−E (4−8).
B
https://dx.doi.org/10.1021/acs.orglett.0c03401
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Subsequent benzylation of the resulting hydroxy groups afforded
17 in 71% overall yield for both steps.10
presence of 3 equiv of pyridine to give biaryl ketone 25 in 54%
overall yield over the two steps.16 Finally, all four benzyl groups
in 25 were removed with Pd/C and ammonium formate to give
the rearrangement precursor 12 in 81% yield. The key
rearrangement reaction of 12, with the required three hydroxy
substituents, proceeded smoothly, as expected, to obtain desired
11 in 88% yield. To remove the phenylacetyl side chain,
phenalenone 11 was converted into mono-MOM-protected 26
in 82% yield. Baeyer−Villiger oxidation followed by ester
hydrolysis afforded the key phenalenone intermediate 27 in 33%
yield over the two steps. Oxidation of phenalenone 27 was then
attempted to achieve the synthesis of triketone 10. Various
oxidations of 27 were carried out, using mCPBA under acidic17
or t-BuOOH under basic conditions,18 air oxidation,19 and
dimethyldioxirane;20 however, only decomposition of 27 was
observed. Therefore, we instead mimicked the biosynthetic
pathway of triketone 105 and investigated oxidation after
removal of the MOM group in 27. Deprotection of 27 with
H2SO4 in CH2Cl2/methanol proceeded to give 28 in 98% yield.
When 28 was treated with mCPBA in EtOAc at 50 °C for 1
week, compound 29 (the methyl ether of lamellicolic
anhydride) was isolated in 11% yield after careful determination
of the structure. The formation of 29 indicated that the desired
triketone 10 was temporarily generated during the oxidation
process. Therefore, we attempted to trap the triketone 10 via an
aldol reaction in the presence of ketonic solvents. First, acetone
was selected, as the simplest ketonic solvent, and oxidation
reactions were examined (Scheme 3A). Treatment of
phenalenone 28 with mCPBA in acetone/EtOAc (1/10) gave
only 29 in 20% yield. In contrast, desired FR-901235 (3) was
afforded with the combination of peracetic acid and acetone/
EtOAc (1/10) in 30% yield. The reason for the different
products can be explained as outlined in Scheme 3B. Either
Imide 17 was hydrolyzed to the acid anhydride using
potassium hydroxide,11 and then this was converted to the
hydroxyimide, which was further treated with p-toluenesulfonyl
chloride to afford the corresponding tosyloxyimide. The
tosyloxyimide was smoothly converted to lactam 18 under
Lossen rearrangement conditions in 81% overall yield over the
three steps from 17.12 Lactam 18 was hydrolyzed with aqueous
NaOH, and the resulting amino group was transformed to a
diazonium salt using nitrate, followed by treatment with acidic
water to afford the lactone 19 via a Sandmeyer-type reaction in
62% yield. Bromination of 19 with NBS proceeded selectively at
the most electron-rich position of the naphthalene ring to give
20 in 92% yield. Lactone 20 was then reduced with NaBH4 to
afford the corresponding phenol alcohol. Due to the low stability
of the alcohol toward air and light, the phenolic hydroxy group
was immediately methylated with dimethyl sulfate to give 21 in
68% yield.13 The benzyl alcohol of 21 was converted to a
mesylate and successively reduced with LiAlH4 to afford the
desired penta-substituted naphthalene 13 in 64% yield over the
two steps.14
The coupling partner, compound 14, was synthesized from 22
(Scheme 1B). Compound 23 was synthesized from 22
according to a reported procedure.15 Both phenolic hydroxy
groups of 23 were protected as benzyl groups to afford 24 in 85%
yield. Compound 24 was then treated with n-butyllithium and
trapped by DMF to afford aldehyde 14 in 80% yield.
With the two naphthalenes 13 and 14 in hand, the coupling
reaction was then carried out (Scheme 2). Penta-substituted
naphthalene 13 was converted to the corresponding aryllithium
using n-butyllithium and reacted with 1.1 equiv of naphthalene
14, delivering the corresponding secondary alcohol, which
wasdue to its instabilitydirectly oxidized by IBX in the
Scheme 3. (A) Optimization of the Oxidization of 28 and (B)
Proposed Mechanisms of Oxidation of Triketone 10
Scheme 2. Synthetic Route from 13 to 28
C
https://dx.doi.org/10.1021/acs.orglett.0c03401
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
mCPBA or peracetic acid oxidized 28 to triketone 10. Triketone
10 was further oxidized in the case of mCPBA to give 29, and in
the case of peracetic acid, overoxidation was suppressed and the
aldol condensation proceeded instead. This is due to the
difference in leaving-group abilities. After addition of peracid to
the central carbonyl group of 10, the corresponding carboxylates
can then be eliminated to complete the Baeyer−Villiger
oxidation. The pKa of acetic acid is 4.76, and that of
chlorobenzoic acid is 3.82; thus, chlorobenzoic acid is a better
leaving group. Therefore, once overoxidation occurred to give
intermediate A, additional oxidation gave the acid anhydride 29.
Conversely, in the case of peracetic acid, the low leaving-group
ability of acetate prevented overoxidation of the triketone 10
and allowed the aldol condensation to proceed.
Conversely, the aldol condensation from compound 5 was
achieved in the presence of piperidine to afford desired
auxarthrone C (6) in 29% yield. Finally, lamellicolic anhydride
(9) was synthesized. Direct demethylation from compound 29
did not proceed, but from compound 28, demethylation under
pyridinium chloride conditions took place to give compound 30
in quantitative yield.7a Then, compound 30 was subjected to
oxidation conditions to afford the desired lamellicolic anhydride
(9) for the first time, in 10% yield. The spectroscopic data of
synthetic FR-901235 (3),3 auxarthrones A−D (4−7), and
lamellicolic anhydride (9) were identical to reported values for
the same compounds isolated from nature.
In conclusion, the first total syntheses of FR-901235 (3),3
auxarthrones A−D (4−7),4 and lamellicolic anhydride (9)5
have been accomplished. These compounds were divergently
synthesized from the common and nonisolated triketone 10.
The main features of these synthetic routes are (1) the
construction of a phenalenone ring possessing the required
functional groups at the necessary positions from the
corresponding dinaphthyl ketone by our originally developed
rearrangement reaction, (2) the suppression of overoxidation of
nonisolated triketone 10 by harnessing the subtle difference in
oxidation ability between peracetic acid and mCPBA, leading to
the desired aldol reactions toward the target compounds, and
(3) the conversion of the labile intermediate triketone 10 to
lamellicolic anhydride (9), which was carried out following the
putative biosynthetic pathway and was achieved synthetically for
the first time. We are now optimizing the synthetic process to
improve the yields and are developing new and more
straightforward methods which will be reported in due course.
Auxarthrones A (4), B (5), and D (7) were constructed by
applying similar synthetic methods (Scheme 4). Compound 28
Scheme 4. Syntheses of Auxarthrones A (4), B (5), C (6), and
D (7) and Lamellicolic Anhydride (9) from Common
Intermediate 28
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03401.
Experimental procedures, analytical data, and copies of
the 1H and 13C NMR spectra for all new products (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Kazunori Tsubaki − Graduate School for Life and
Environmental Sciences, Kyoto Prefectural University, Kyoto
606-8522, Japan; orcid.org/0000-0001-8181-0854;
Email: tsubaki@kpu.ac.jp
Authors
Kotaro Kiyotaki − Graduate School for Life and Environmental
Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan
Takuto Kayukawa − Graduate School for Life and
Environmental Sciences, Kyoto Prefectural University, Kyoto
606-8522, Japan
Ayumi Imayoshi − Graduate School for Life and Environmental
Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan
was treated with peracetic acid in a mixture of ethyl methyl
ketone/EtOAc (1/10) to afford auxarthrone A (4) and
auxarthrone B (5) in 17 and 4% yields, respectively. Similarly,
auxarthrone D (7) was synthesized from 28 and diethyl ketone
in 24% yield. Next, intramolecular aldol condensations from 5
and 7 were examined. Although various conditions were applied
to 7, it was highly unstable under basic conditions, and the
desired compound 8 could not be obtained. Under basic
conditions, retro-aldol reaction with elimination of the diethyl
ketone moiety proceeded instead (see Supporting Information).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03401
Notes
The authors declare no competing financial interest.
D
https://dx.doi.org/10.1021/acs.orglett.0c03401
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
1164. (c) Yonekawa, M.; Furusho, Y.; Sei, Y.; Takata, T.; Endo, T. The
Chemistry of Vicinal Polycarbonyl Compounds. Tetrahedron 2013, 69,
4076−4080.
(10) Xue, J. Y.; Nakanishi, W.; Tanimoto, D.; Hara, D.; Nakamura, Y.;
Isobe, H. Convergent Synthesis of Hexameric Naphthylene Macro-
cycles with Dicarboxylic Imide Appendages. Tetrahedron Lett. 2013, 54,
4963−4965.
ACKNOWLEDGMENTS
■
The authors are grateful to Ms. Kyohko Ohmine (ICR, Kyoto
University) and Ms. Ayaka Maeno (ICR, Kyoto University) for
the NMR measurements, and Prof. Yoshihiro Ueda (ICR, Kyoto
University) and Ms. Akiko Fujihashi (ICR, Kyoto University)
for the high-resolution mass spectrometry. This study was
carried out using the Fourier transform ion cyclotron resonance
mass spectrometer and NMR in the Joint Usage/Research
Centre at the Institute for Chemical Research, Kyoto University.
This study was supported in part by JSPS KAKENHI
(18K19150) and Grant-in-Aid from the Tokyo Biochemical
Research Foundation (16-A1-2). The authors thank Alison
McGonagle, PhD, for editing a draft of this manuscript.
(11) Dyar, S. M.; Margulies, E. A.; Horwitz, N. E.; Brown, K. E.;
Krzyaniak, M. D.; Wasielewski, M. R. Photogenerated Quartet State
Formation in a Compact Ring-Fused Perylene-Nitroxide. J. Phys. Chem.
B 2015, 119, 13560−13569.
̈
(12) Cammidge, A. N.; Ozturk. Selective Synthesis of meso-
̈
Naphthylporphyrins. O. J. Org. Chem. 2002, 67, 7457−7464.
(13) Masquelin, T.; Hengartner, U.; Streith, J. Coccidiostatic Agents:
Synthesis of some Analogs of ( )-Frenolicin B. Synthesis 1995, 1995,
780−786.
(14) Padwa, A.; Dimitroff, M.; Liu, B. Formal Synthesis of
( )-Dendrobine: Use of the Amidofuran Cycloaddition/ Rearrange-
ment Sequence. Org. Lett. 2000, 2, 3233−3235.
(15) Martinborough, E.; Denti, T. M.; Castro, P. P.; Wyman, T. B.;
Knobler, C. B.; Diederich, F. Chiral 1,l’-Binaphthyl Molecular Clefts for
the Complexation of Excitatory Amino-Acid Derivatives. Helv. Chim.
Acta 1995, 78, 1037−1066.
(16) Frigerio, M.; Santagostino, M.; Sputore, S. A User-Friendly Entry
to 2-Iodoxybenzoic Acid (IBX). J. Org. Chem. 1999, 64, 4537−4538.
(17) (a) Detering, J.; Martin, H. D. 4,6,6-Trimethyl-4-cyclohexene-
1,2,3-trione, a Contoribution to the Biogenesis of Norcarotinoids.
Angew. Chem., Int. Ed. Engl. 1988, 27, 695−698. (b) Tsuchikama, K.;
Lowery, C. A.; Janda, K. D. Probing Autoin-ducer-2 Based Quorum
Sensing: The Biological Consequences of Molecules Unable to
Traverse Equilibrium States. J. Org. Chem. 2011, 76, 6981−6989.
(18) Cooke, R. G.; Dagley, I. J. Colouring Matters of Australian Plants.
XX Synthesis of Hydroxyanigorufone and Related Phenalenones. Aust.
J. Chem. 1978, 31, 193−197.
REFERENCES
■
(1) Sasaki, S.; Azuma, E.; Sasamori, T.; Tokitoh, N.; Kuramochi, K.;
Tsubaki, K. Formation of Phenalenone Skeleton by an Unusual
Rearrangement Reaction. Org. Lett. 2017, 19, 4846−4849.
(2) (a) Azuma, E.; Nakamura, M.; Kuramochi, K.; Sasamori, T.;
Tokitoh, N.; Sagami, I.; Tsubaki, K. Exhaustive Syntheses of
Naphthofluoresceins and Their Functions. J. Org. Chem. 2012, 77,
3492−3500. (b) Yamashita, H.; Minari, C.; Azuma, E.; Kuramochi, K.;
Imayoshi, A.; Tsubaki, K. Synthesis and Optical Properties of L-Shaped
Dinaphthofluoresceins with Two Peripheral Hydroxy Groups. Hetero-
cycles 2020, 101, 536−546.
(3) Shibata, T.; Nishikawa, M.; Tsurumi, Y.; Takase, S.; Terano, H.;
Kohsaka, M. New Immunomodulator, FR-901235. J. Antibiot. 1989, 42,
1356−1361.
(4) Li, Y.; Yue, Q.; Jayanetti, D. R.; Swenson, D. C.; Bartholomeusz, G.
A.; An, Z.; Gloer, J. B.; Bills, G. F. Anti-Cryptococcus Phenalenones and
Cyclic Tetrapeptides from Auxarthron pseudauxarthron. J. Nat. Prod.
2017, 80, 2101−2109.
(5) McCorkindale; McRitchie, N. J. A.; Hutchinson, S. A. Larnellicolic
Anhydride − a Heptaketide Naphthalic Anhydride from Verticillium
Lamellicola. J. Chem. Soc., Chem. Commun. 1973, 108−109.
(6) Elsebai, M. F.; Saleem, M.; Tejesvi, M. V.; Kajula, M.; Mat-tila, S.;
Mehiri, M.; Turpeinen, A.; Pirttila, A. M. Fungal Phenalenones:
Chemistry, Biology, Biosynthesis and Phylogeny. Nat. Prod. Rep. 2014,
31, 628−645.
(19) Chen, Y.; Paetz, C.; Menezes, R. C.; Schneider, B. Cultured
Roots of Xiphidium Caeruleum: Phenylphenalenones and Their
Biosynthetic and Extractant-dependent Conversion. Phytochemistry
2017, 133, 15−25.
(20) Kawamura, M.; Kamo, S.; Azuma, S.; Kubo, K.; Sasamori, T.;
Tokitoh, N.; Kuramochi, K.; Tsubaki, K. Skeletal Rearrangements of
Polycyclic α-Ketols. Org. Lett. 2017, 19, 301−303.
̈
(7) (a) Gao, S.-S.; Zhang, T.; Garcia-Borras, M.; Hung, Y.-S.;
Billingsley, J. M.; Houk, K. N.; Hu, Y.; Tang, Y. Biosynthesis of
Heptacyclic Duclauxins Requires Extensive Redox Modifications of the
Phenalenone Aromatic Polyketide. J. Am. Chem. Soc. 2018, 140, 6991−
6997. (b) Cao, P.; Yang, J.; Miao, C. P.; Yan, Y.; Ma, Y. T.; Li, X. N.;
Zhao, L. X.; Huang, S. X. New Duclauxamide from Penicillium manginii
YIM PH30375 and Structure Revision of the Duclauxin Family. Org.
Lett. 2015, 17, 1146−1149. (c) Gao, S. S.; Duan, A.; Xu, W.; Yu, P.;
Hang, L.; Houk, K. N.; Tang, Y. The Radical SAM Enzyme HydG
Requires Cysteine and a Dangler Iron for Generating an Organo-
metallic Precursor to the [FeFe]-Hydrogenase H-Cluster. J. Am. Chem.
Soc. 2016, 138, 4249−4259.
(8) (a) McCorkindale, N.J.; Hutchinson, S.A.; McRitchie, A.C.; Sood,
G.R. Lamellicolic Anhydride, 4-O-Carbomethoxy Lamellicolic Anhy-
dride and Monomethyl 3-Chlorolamellicolate, Metabolites of Verti-
cillium Lamellicola. Tetrahedron 1983, 39, 2283−2288. (b) Elsebai, M.
F.; Kehraus, S.; Lindequist, U.; Sasse, F.; Shaaban, S.; Gutschow, M.;
̈
̈
Josten, M.; Sahl, H. G.; Konig, G. M. Antimicrobial Pphenalenone
Derivatives from the Marine-derived Fungus Coniothyrium cereale. Org.
Biomol. Chem. 2011, 9, 802−808. (c) Nazir, M.; El Maddah, F.;
Kehraus, S.; Egereva, E.; Piel, J.; Brachmann, A. O.; Konig, G. M.
Phenalenones: Insight into the Biosynthesis of Polyketides from the
Marine Alga-derived Fungus Coniothyrium cereale. Org. Biomol. Chem.
2015, 13, 8071−8079.
(9) (a) Matsushita, K.; Suzuki, K.; Ohmori, K. Total Syntheses of
Atrovenetin and Atrovenetinone: A Naphthalene-Annulation Ap-
proach to a Discoid Tricycle Using Allenic Acid. Synlett 2017, 28,
944−950. (b) Rubin, M. B.; Gleiter, R. Chem. Rev. 2000, 100, 1121−
E
https://dx.doi.org/10.1021/acs.orglett.0c03401
Org. Lett. XXXX, XXX, XXX−XXX