Total synthesis of mansonone e

Article abstract of DOI:10.3184/174751914X13899760861508

The synthesis of mansonone E was completed in six steps and 34% overall yield from commercially available starting material 3-bromo-4-methyl acetophenone. The thermal ring expansion of a cyclobutenedione derivative followed by an intramolecular 1,3-alkoxy exchange provided a facile route to the 1,2-naphthoquinone tricyclic structure of mansonone E.

Full text of DOI:10.3184/174751914X13899760861508

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 MARCH, 137–139
RESEARCH PAPER 137
Total synthesis of mansonone E
Xianhe Fang and Xiangdong Hu*
Department of Chemistry & Material Science, Key Laboratory of Synthetic and Natural, Functional Molecule Chemistry of Ministry of Education
of China, Northwest University, 229 N. Taibai Road Xi’an 710069, P.R. China.
The synthesis of mansonone E was completed in six steps and 34% overall yield from commercially available starting material
3‑bromo‑4‑methyl acetophenone. The thermal ring expansion of a cyclobutenedione derivative followed by an intramolecular
1,3‑alkoxy exchange provided a facile route to the 1,2‑naphthoquinone tricyclic structure of mansonone E.
Keywords: total synthesis, natural products, ring expansion, cyclisation, quinones
Mansonone E (1 in Fig. 1) was first isolated from the heartwood
R
O
A
O
Me
B
O
O
sawdust of Mansonia altissima1 and then from Ulmus
hollandica,2 Thespesia populnea,3 and traditional medicinal
plantssuchasUlmusdavidiana,4 Alangiumchinense,5 Mansonia
gagei,6 and Helicteres angustifolia.7 Mansonone E exhibited
fungitoxic,2 antibacterial,3 antileukaemic,4 and antioxidant8
activity. In addition, mansonone E showed significant cytotoxic
activities against human cancer cell lines MCF-7 (IC50ꢀ=ꢀ0.05ꢀμgꢀ
mL–1), HeLa (IC50ꢀ=ꢀ0.55ꢀμgꢀmL–1), HT-29 (IC50ꢀ=ꢀ0.18ꢀμgꢀmL–1),
and KB (IC50ꢀ=ꢀ0.40ꢀμgꢀmL–1).3
O
O
Me
R1
Me
C
Me
Me
R2
mansonone F (5) R=H
mansonone L (6) R=OH
mansonone E (1) R1=H R2=H
mansonone H (2) R1=OH R2=H
mansonone I (3) R1=H R2=OH
mansonone M (4) R1=OMe R2=H
Mansonone E (1) is a tricyclic sesquiterpenoid containing a
1,2-naphthoquinone moiety. Mansonones F (5), H (2), I (3), L
(6), and M (4) contain the same chemical scaffold. Mansonone
has attracted the attention of synthetic chemists because of
these interesting biological activities and its unique structural
features. To date, two basic strategies have been employed in
mansonone synthesis:9–12 (i) the intramolecular Diels–Alder
reaction between benzynes and furans developed by Wege9 and
utilised for the synthesis of mansonones E, F, and I;10 and (ii)
the intramolecular Friedel–Crafts reaction of multi-substituted
naphthalenes which was used for the synthesis of mansonone F
by Suh11 and Bieber12. So far, the oxidation of multi-substituted
tricyclic naphthalenes has been applied for the construction of
the 1,2-naphthoquinone moiety.9–12
Fig. 1 Structures of mansonones E, F, H, I, L and M.
cyclobutenedione derivative has been applied to the total
synthesisꢀofꢀ(−)-mansononeꢀBꢀbyꢀHarrowven’sꢀgroup.ꢀNotably,ꢀ
an impressive regioselectivity-reversed addition of organo-
ytterbium reagent to cyclobutenedione was developed in their
work.17 Our retrosynthetic analysis of mansonone E is shown
in Scheme 1. The thermal ring expansion of cyclobutenedione
derivative 8, which was synthesised by the addition of the
aromatic lithium 10 to the cyclobutenedione 9,18,19 will afford
the 1,4-naphthoquinone 7. The intramolecular 1,3-alkoxy
exchange of the 1,4-naphthoquinone moiety of 7 will afford the
1,2-naphthoquinone moiety and ring C of 1.
The aromatic lithium 10 was prepared starting from
the methylenation of commercially available 3-bromo-4-
methylacetophenone 14 (Scheme 2). The hydroboration–
oxidation of 13 and the protection of the resulting hydroxyl
group readily afforded compound 11 in 97% overall yield over
three steps.
Results and discussion
We now report a new synthetic route to 1 by the thermal ring
expansion of a cyclobutenedione derivative developed by
Moore13,14 and Liebeskind15,16 and the intramolecular 1,3-alkoxy-
exchange-assisted synthesis of the 1,2-naphthoquinone
moiety and ring C. Recently, the thermal ring expansion of
O
O
intramolecular
1,3-alkoxyl exchange
O
O
thermal ring
expansion
O
OR
O
7
1
O
Li
O
O
O
O
HO
+
OR
OR
9
10
8
Scheme 1 Retrosynthetic pathway for mansonone E.
* Correspondent. E-mail: xiangdonghu@nwu.edu.cn

138ꢀꢀꢀJOURNALꢀOFꢀCHEMICALꢀRESEARCHꢀ2014
Me
Me
Me
Me
Br
Br
Br
Br
a
b
c
OTBS
OH
O
13
11
14
12
Scheme 2 (a) THF, Ph3P=CH2, room temperature; (b) BH3THF, THF, –10 °C, then aq.
NaOH, H2O2; (c) TBSCl, Et3N, CH2Cl2, 0.1 equiv. DMAP (4‑dimethylaminopyridine), 97%
over three steps.
The addition of aromatic lithium 10, formed in situ by the
Having obtained 1,4-naphthoquinone 7, the last task was
to construct ring C and the 1,2-naphthoquinone moiety of
the target. We first planned to remove the TBS protecting
group and then carry out the proposed 1,3-alkoxy exchange
reaction. Fortunately, the treatment of 7 with HCl in
methanol simultaneously resulted in deprotection and the
intramolecular 1,3-alkoxy-exchange-assisted synthesis of the
1,2-naphthoquinone moiety and ring C (Scheme 4). Thus, 1
was obtained in 90% yield.
treatment of 11 with n-butyllithium, to cyclobutenedione 9
afforded smoothly cyclobutenedione derivative 8.ꢀNext,ꢀ8 was
directly subjected to a thermal ring expansion without further
purification because it decomposed on silica gel. In refluxing
toluene, 8 afforded intermediate 15 by a 4-electron electrocyclic
ringꢀopening/6-electronꢀelectrocyclicꢀcascade.ꢀNext,ꢀoxidationꢀ
of 15 using DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone)
afforded 1,4-naphthoquinone 7, as the final product, in 39%
overall yield starting from 11 (Scheme 3).
O
O
OH
Br
Li
O
O
9
d
O
OTBS
OTBS
OTBS
OH
11
10
O
8
four-electron
electrocyclic ring
opening
six-electron
electrocyclic ring
closure
C
O
e
OTBS
O
O
OH
O
O
DDQ
OTBS
OH
15
OTBS
7
Scheme 3 Synthesis of 7 (d) n‑BuLi, THF, –78 °C, 5 min, then 9; (e) toluene, reflux, then
DDQ, 39% from 11.
O
O
O
O
H
O
O
f
–H2O
HO
O
O
O
OTBS
H
OH
7
O
O
O
O
H2O
O
–MeOH
O
mansonone E (1)
Scheme 4 Synthesis of 1 (f) HCl, MeOH, 90% yield.

JOURNALꢀOFꢀCHEMICALꢀRESEARCHꢀ2014ꢀꢀꢀ139
(100 MHz, CDCl3),ꢀδꢀ 189.07,ꢀ183.57,ꢀ157.34,ꢀ145.34,ꢀ 138.78,ꢀ136.09,ꢀ
133.27, 131.80, 130.87, 130.34, 67.80, 60.41, 36.33, 25.86, 23.03, 18.24,
17.75, 9.29, 5.51. HRMS (ESI) calcd for C22H32NaO4Siꢀ [Mꢀ+ꢀNa]+
411.1968, found 411.1965.
Conclusions
In summary, the combination of a thermal ring expansion of a
cyclobutenedione derivative and 1,3-alkoxyl exchange assisted
formation of 1,2-naphthoquinone motif and ring C led to the
formation of 1,2-naphthoquinone motif and ring C. This has
proved to be an efficient protocol to synthesise the molecular
skeleton of mansonone E. The total synthesis of mansonone E
has been accomplished in six steps and 34% overall yield.
Mansonone E (1): One drop of concentrated HCl was added to a
solution of 7 (60 mg) in methanol (5 mL). The yellow colour turned to
orange immediately. After 20 min the reaction was quenched with 5%
aq.ꢀNaHCO3 (10 mL), extracted with ethyl acetate (3×10 mL), dried
overꢀanhydrousꢀNa2SO4, and evaporated to dryness. The residue was
purified by flash chromatography (SiO2, petroleum ether to petroleum
ether/ethyl acetate 5:1) to give mansonone E as orange–yellow needles
(33ꢀmg,ꢀ90%).ꢀIRꢀλmax (KBr) cm–1: 2922, 1692, 1642, 1612, 1577, 1347,
1286, 1174, 947. 1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl3)ꢀδꢀ7.35ꢀ(d,ꢀJ=8 Hz, 1 H),
7.26 (d, J=8 Hz, 1 H), 4.41 (dd, J=10.7, 4.0 Hz, 1 H), 4.23 (dd, J=10.8,
5.2 Hz, 1 H), 3.10 (m, 1 H), 2.65 (s, 3 H), 1.96 (s, 3 H), 1.37 (d, J=7.1 Hz,
3 H). 13CꢀNMRꢀ(100ꢀMHz,ꢀCDCl3),ꢀδꢀ182.11,ꢀ180.08,ꢀ162.49,ꢀ142.78,ꢀ
136.85, 134.83, 132.62, 127.19, 126.74, 116.09, 71.36, 31.20, 22.48,
17.50, 7.73. HRMS (ESI) calcd for C15H14NaO3ꢀ [Mꢀ+ꢀNa]+ 265.0841,
found 265.0842.
Experimental
NMRꢀ spectraꢀ wereꢀ recordedꢀ onꢀ Varianꢀ INOVA-400ꢀMHzꢀ
spectrometers. 1HꢀNMRꢀ(400ꢀMHz)ꢀspectraꢀwereꢀreferencedꢀtoꢀCDCl3
(7.26 ppm) and 13CꢀNMRꢀ(100ꢀMHz)ꢀspectraꢀwereꢀreferencedꢀtoꢀCDCl3
(77.0 ppm). Mass spectra were obtained using electrospray ionisation
(ESI) UltiMate3000 mass spectrometer. THF was dried by sodium
benzophenone and distilled under argon. Reactions were carried out in
flamed reaction flasks, connected to a vacuum-argon line when THF
as solvent. Yields refer to chromatographically purified products.
11: n-Butyllithium (4.2 mL, 10.1 mmol, 2.4 M in hexanes) was added
at room temperature to a solution of methyltriphenylphosphonium
bromide (3.65 g, 10.2 mmol) in THF (100 mL). After being
stirred for 2 h, yellow solution was obtained, and 3-bromo-4-
methylacetophenone 14 (1.81 g, 8.54 mmol) was added. After being
stirred for 1 day, the solution was evaporated under reduced pressure,
the residue was purified by short flash chromatography (SiO2,
petroleum ether). The colourless oil was dissolved in THF (40 mL) and
cooled to –10 °C, and treated dropwise with BH3 (9.3 mL, 9.3 mmol,
1 M in THF). The resulting mixture was stirred at this temperature
forꢀ2ꢀh,ꢀthenꢀtreatedꢀwithꢀ10%ꢀNaOHꢀ(12ꢀmL).ꢀAfterꢀ30ꢀmin,ꢀ30%ꢀH2O2
(6.5 mL) was added, and the mixture was stirred at room temperature
for 2 h. Brine (50 mL) was added, and the mixture was extracted with
ethyl acetate (3×50 mL). The combined organic layers were dried
overꢀanhydrousꢀNa2SO4, and evaporated to dryness. The residue was
dissolved in CH2Cl2 (40 mL) and TBSCl (1.93 g, 12.8 mmol), Et3Nꢀ
(1.19 mL, 17 mmol), DMAP (100 mg, 0.8 mmol) were added. The
reaction was stirred overnight and washed with H2O (20 mL). The
organicꢀlayerꢀwasꢀdriedꢀoverꢀanhydrousꢀNa2SO4, and evaporated to
dryness. Purification by flash chromatography (SiO2, hexane) gave
11ꢀasꢀaꢀcolourlessꢀoilꢀ(2.87ꢀg,ꢀ97%).ꢀIRꢀλmax (KBr) cm–1: 2954, 2856,
1465, 1253, 1093, 839. 1HꢀNMRꢀ(400ꢀMHz,ꢀCDCl3)ꢀδꢀ7.39ꢀ(s,ꢀ1ꢀH),ꢀ7.13ꢀ
(d, J=7.6 Hz, 1 H), 7.05 (d, J=7.3 Hz, 1 H), 2.83 (m, 1 H), 3.63 (dd,
J=9.6, 6.2 Hz, 1 H), 3.56 (dd, J=9.6, 7.1 Hz, 1 H), 2.35 (s, 3 H), 1.24 (d,
J=6.9 Hz, 3 H), 0.86 (s, 9 H), –0.03 (s, 3 H), –0.04 (s, 3 H). 13CꢀNMRꢀ
(100 MHz, CDCl3),ꢀδꢀ144.06,ꢀ135.41,ꢀ131.40,ꢀ130.42,ꢀ126.52,ꢀ124.62,ꢀ
68.92, 41.67, 25.87, 22.44, 18.27, 17.35, 5.49. HRMS (ESI) calcd for
C16H27BrNaOSiꢀ[Mꢀ+ꢀNa]+ 365.0912, found 365.0906.
WeꢀareꢀgratefulꢀforꢀfinancialꢀsupportꢀfromꢀtheꢀNationalꢀNaturalꢀ
ScienceꢀFoundationꢀofꢀChinaꢀ(NSF-21002078,ꢀ21372184),ꢀtheꢀ
PhD Programs Foundation for young teachers of the Ministry
of Education of China (20106101120004), the Education
Departmentꢀ ofꢀ Shaanxiꢀ Provinceꢀ (2010JK873),ꢀ Northwestꢀ
University (PR11025), and the Open Foundation from the Key
Laboratoryꢀ ofꢀ Syntheticꢀ andꢀ Naturalꢀ Functionalꢀ Moleculeꢀ
Chemistry of the Ministry of Education.
Electronic Supplementary Information
The ESI is available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data.
Received 12 December 2013; accepted 7 January 2014
Paper 1302332 doi: 10.3184/174751914X13899760861508
Published online: 7 March 2014
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