Facile construction of the oxaphenalene skeleton by peri ring closure. Formal synthesis of mansonone F

Article abstract of DOI:10.1039/b001859g

A concise and divergent total synthesis of mansonone F has been accomplished via an efficient construction of the oxaphenalene skeleton by facile peri ring closure of the naphthol ether, and an effective preparation of the cyclization precursor starting from readily available 5-methoxy-1- tetralone by employing a palladium-induced aromatization of the naphthalinol.

Full text of DOI:10.1039/b001859g

Facile construction of the oxaphenalene skeleton by peri ring closure. Formal
synthesis of mansonone F
Young-Ger Suh,* Dong-Yun Shin, Kyung-Hoon Min, Soon-Sil Hyun, Jae-Kyung Jung and Seung-Yong Seo
College of Pharmacy, Seoul National University, San 56-1, Shinrim-Dong, Kwanak-Gu, Seoul 151-742, Korea.
E-mail: YGSUH@plaza.snu.ac.kr
Received (in Cambridge, UK) 7th March 2000, Accepted 16th May 2000
A concise and divergent total synthesis of mansonone F has
been accomplished via an efficient construction of the
oxaphenalene skeleton by facile peri ring closure of the
naphthol ether, and an effective preparation of the cycliza-
tion precursor starting from readily available 5-methoxy-
1-tetralone by employing a palladium-induced aromatiza-
tion of the naphthalinol.
substituent corresponding to the C9-methyl of mansonone F
was effectively introduced by benzeneboronic acid-assisted
hydroxymethylation10 followed by hydrogenolysis of the
resulting benzyl alcohol. O-alkylation of the naphthol 6 with
bromoacetate afforded the dimethylnaphthol ether 2 as a
cyclization precursor. The key tricyclic oxaphenalene skeleton
of mansonone F was efficiently constructed by a facile peri ring
closure8 of the dimethylnaphthol ether 2. Conversion of the
ester 2 to an acid halide and then intramolecular Friedel–Crafts
Mansonone F (1) and biflorin, which are members of the
naturally occurring ortho-naphthoquinone family, contain the
unusual oxaphenalene skeleton.1 Biflorin, the first oxaphena-
lene natural product, was found to have antibiotic properties.2
More interestingly, mansonone F, a tricyclic sesquiterpenoid,
has been reported as a phytoalexin325 which is accumulated in
the heartwood of the genus Ulmus in response to infections.
Recently, mansonone F has also been isolated from the root bark
of Ulmus davidiana, which has been traditionally used as a
medicinal plant for treatment of infections in Korea. In addition,
the highly potent anti-MRSA activity of mansonone F,
comparable to that of vancomycin, has been studied in our
laboratory.6 However, the paucity of natural mansonone F, as
well as its inherent structural constraint, has limited the
optimization of its biological properties by structural modifica-
tion and its therapeutic application. These reasons prompted us
to develop a practical and divergent synthetic route to
mansonone F, although an elegant synthesis of mansonone F
employing intramolecular Diels–Alder addition of benzynes to
furans has already been reported.7 We report herein a concise
and divergent synthesis of mansonone F starting from readily
available 5-methoxy-1-tetralone.
Scheme 1 Synthetic strategy.
Our synthetic strategy (Scheme 1) envisions a highly efficient
construction of the tricyclic oxaphenalene skeleton via peri ring
closure8 by an intramolecular Friedel–Crafts acylation of the
dimethylnaphthol ether 2 or 3. The cyclization precursors 2 and
3 are readily accessible from the commercially available
methoxytetralone 5 by sequential introduction of the alkyl
substituents and an effective aromatization of the tetralinol
intermediate.
Our synthesis (Scheme 2) commenced with preparation of the
methylnaphthol 4. The first methyl substituent, corresponding
to the C6-methyl of mansonone F, was conveniently introduced
by methyl Grignard addition to the carbonyl of the tetralone 5.
Aromatization9 of the resulting carbinol by palladium-induced
concurrent dehydration and dehydrogenation and then deme-
thylation of the resulting methoxynaphthalene by boron tri-
bromide provided the methylnaphthol 4. The methylnaphthol 4
was transformed in a straightforward manner into the cycliza-
tion precursor 2 by a three step sequence. The second methyl
Scheme 2 First synthetic route to mansonone F. Reagents and conditions: i,
MeMgI, Et2O, reflux, 1 h; ii, 10% Pd/C, triglyme, reflux, 2 days; iii, BBr3,
CH2Cl2, 278 °C, then warm to room temp. (94% in 3 steps); iv, PhB(OH)2,
(CHO)n, propionic acid, PhH, reflux, 1 h, then H2O2, THF; v, 10% Pd/C, H2,
MeOH, 5 h (63% in 2 steps); vi, BrCH2CO2Me, K2CO3, acetone, reflux
(82%); vii, LiOH·H2O, THF–H2O, 10 min; viii, (COCl)2, PhH, reflux, 1 h,
then AlCl3, CH2Cl2 (74% in 2 steps).
DOI: 10.1039/b001859g
Chem. Commun., 2000, 1203–1204
This journal is © The Royal Society of Chemistry 2000
1203

by halogen–metal exchange followed by methylation. Finally,
construction of the oxaphenalene skeleton was executed by
facile peri ring closure induced by polyphosphoric acid, to give
the key intermediate 10. In order to complete the synthesis, the
ortho-quinone moiety of mansonone F was elaborated by
application of the reported procedure.7 The synthetic man-
sonone F was identical in all aspects to the naturally occuring
compound.1,10
In summary, the total synthesis of mansonone F has been
accomplished via a 10 step sequence, starting from the readily
available 5-methoxy-1-tetralone (5). The key part of this
synthesis involves the efficient preparation of 1,6-dimethyl-
5-alkoxynaphthalene as a divergent cyclization precursor and
its facile conversion to form the oxaphenalene skeleton by peri
ring closure. This concise and practical synthetic procedure,
providing a variety of substituents at the C3, C6 and C9
positions, offers a useful synthetic route to this important
prospective anti-MRSA drug.
This research was supported by grant CHMP-00-CH-
15-0014 from the Ministry of Health & Welfare and in part by
1999 BK21 project for Medicine, Dentistry and Pharmacy.
Notes and references
1 R. H. Thomson, Naturally Occurring Quinones, Academic Press,
London, 1971, 198.
2 O. Goncalves de Lima, W. Keller-Schierlein and V. Prelog, Helv. Chim.
Acta, 1958, 41, 1386.
3 J. C. Overeem and D. M. Elgersma, Phytochemistry, 1970, 9, 1949.
4 M. T. Dumas, G. M. Strunz, S. M. Hubbes and R. S. Jeng, Experimentia,
1983, 39, 1089.
Scheme 3 Alternative synthetic route to mansonone F. Reagents and
conditions: i, NBS, CH2Cl2, 0 °C (60–70%); ii, BrCH2COMe, K2CO3,
acetone, reflux (96%); iii, (CH2OH)2, PTSA, PhH, reflux (89%); iv, BunLi,
MeI, THF, 278 °C, then warm to room temp. (95%); v, PPA, 100 °C (87%);
vi, Cu(NO3)2·xH2O, Ac2O (83%); vii, 10% Pd/C, NaBH4, MeOH, then
Fremy’s salt, 0.06 M NaH2PO4, acetone (41%).
5 L. C. Duchesne, R. S. Jeng and M. Hubbes, Can. J. Bot., 1984, 63,
678.
6 Unpublished results. H. S. Kim, PhD dissertation, Seoul National
University, 1999.
7 W. M. Best and D. Wege, Aust. J. Chem., 1986, 39, 647.
8 R. Adams, Org. React., 1957, 2, 114.
9 W. Dai, E. Abu-Shqara and R. G. Harvey, J. Org. Chem., 1995, 60,
4905.
acylation of the acid halide afforded the advanced intermediate
7, which was transformed into mansonone F by a known
procedure.7
Our alternative synthetic route for the transformation of
methylnaphthol 4 into mansonone F is summarized in Scheme
3. The tether for peri ring closure was introduced to the
bromonaphthol 8 by sequential O-alkylation with bromoace-
tone and carbonyl protection. Addition of the methyl substituent
corresponding to the C9-methyl of mansonone F was achieved
10 G. B. M. Bettòlo, C. G. Casinovi and C. Galeffic, Tetrahedron Lett.,
1965, 4857.
1204
Chem. Commun., 2000, 1203–1204