Synthesis of demethylated nidulol via an intramolecular Michael reaction

Article abstract of DOI:10.1080/14786410903458265

An expeditious synthesis of 5,7-dihydroxy-6-methylphthalide from open-chain precursors is described. The key intermediates, synthons 3 and 4, were readily obtained from accessible materials and were further transformed to a common precursor, a five-membered lactone derivative, via an intramolecular Michael addition. Lactone 2 was aromatised to the phthalide system under basic conditions. The process thus constitutes a formal synthesis of the phthalide framework.

Full text of DOI:10.1080/14786410903458265

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Synthesis of demethylated nidulol via
an intramolecular Michael reaction
a
b
Rogelio Jiménez , Luís A. Maldonado & Héctor Salgado-Zamora
a
a
Departamento de Química Orgánica, Escuela Nacional de
Ciencias Biológicas, Instituto Politécnico Nacional, Prolongacion
Carpio y Plan de Ayala S/N, 11340 México D.F., Mexico
b
Instituto de Química, UNAM, Coyoacán 04510, México D.F.,
Mexico
Version of record first published: 19 Jul 2010.
To cite this article: Rogelio Jiménez , Luís A. Maldonado & Héctor Salgado-Zamora (2010):
Synthesis of demethylated nidulol via an intramolecular Michael reaction, Natural Product
Research: Formerly Natural Product Letters, 24:13, 1274-1281
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Natural Product Research
Vol. 24, No. 13, 15 August 2010, 1274–1281
Synthesis of demethylated nidulol via an intramolecular
Michael reaction
a
b
s A. Maldonado and Hector Salgado-Zamora
´ ´
a
Rogelio Jime
´
nez *, Luı
a
Departamento de Quı ´m ica Orga´nica, Escuela Nacional de Ciencias Biolo´gicas, Instituto
Polite´cnico Nacional, Prolongacion Carpio y Plan de Ayala S/N, 11340 Me´xico D.F.,
b
Mexico; Instituto de Quı ´m ica, UNAM, Coyoaca´n 04510, Me´xico D.F., Mexico
(
Received 8 September 2009; final version received 2 November 2009)
An expeditious synthesis of 5,7-dihydroxy-6-methylphthalide from
open-chain precursors is described. The key intermediates, synthons 3 and
4, were readily obtained from accessible materials and were further
transformed to a common precursor, a five-membered lactone derivative,
via an intramolecular Michael addition. Lactone 2 was aromatised to the
phthalide system under basic conditions. The process thus constitutes
a formal synthesis of the phthalide framework.
Keywords: phthalides; nidulol; intramolecular aromatisation
1
. Introduction
Phthalides (1H-2,3-dihydroisobenzofuran-1-ones) constitute the molecular skeleton
of many natural products. The 5,6,7-substituted phthalides form a family of natural
phytotoxins possessing this heterocyclic unit. They are produced by some lichens of
the Alternaria genus, which may inflict severe spoilage on commercially important
plants. Alternaria porri (Hariprakasha & Subba Rao, 1998), for example, causes dark
spots on onions and other plants, and Alternaria zinniae (Hariprakasha & Subba
Rao, 1998; Nozawa, Seyea, Nakajima, Udagawa, & Kawai, 1987) attacks the
sunflower stem and leaves. Extracts of Aleatoria nigricans (Solberg, 1975) show toxic
effects on chicken and mouse embryos. Nidulol (1a) and demethylnidulol (1b)
(Figure 1) were isolated from natural sources (Aspergillus nidulans (Aucamp &
Holzapfel, 1968) and Aspergillus duricaulis (Elix & Joyanthi, 1987)). In a synthetic
sequence aimed to elucidate the structure of lichen metabolites, both products were
obtained as well (Achenbach, Muehlenfeld, & Brillinger, 1985).
Reported procedures that aimed to synthesise 5,6,7-trisubstituted and 4,5,6,7-
tetrasubstituted phthalides are abundant and may be grouped in well-defined
strategies. In one approach, a substituted benzene is the starting material on which
the construction of the five-membered lactone follows (Kobayashi, Shimizu, Itoh,
&
1
Suginome, 1990; Lee, et al., 2001; Makara, Klubek, & Anderson, 1996; Patterson,
995). Another approach considers the simultaneous formation of the five- and
*Corresponding author. Email: rogelio_jj48@yahoo.com.mx
ISSN 1478–6419 print/ISSN 1029–2349 online
ß 2010 Taylor & Francis
DOI: 10.1080/14786410903458265
http://www.informaworld.com

Natural Product Research
1275
OR
O
Me
HO
O
Figure 1. 1a, R
1
¼ Me, nidulol, 1b, R
1
¼ H, demethylated nidulol.
O
O
O
R2
R2
O
O
O
O
R1
R1
OEt
Scheme 1. Synthesis of phthalide derivatives via intramolecular condensations.
six-membered rings via a Diels–Alder reaction (Cruz, Talamas, Va
´
zquez, &
Muchowski, 1997; Watanabe, Tsukazaki, Hamada, Iwao, & Furukawa, 1989) or
intramolecular condensations (Covarrubias-Zuniga et al., 2003, 2005). In the
˜
synthetic strategy depicted further (Scheme 1), the five-membered ring is first
obtained through an aldol condensation, then the phenyl ring is constructed by a
Dieckmann condensation (Auricchio, Ricca, & de Pava, 1983).
Herein, an approach for the synthesis of metabolite 1b (5,7-dihydroxy-
-methylisobenzofuran-2-one), similar to the aforementioned synthetic strategy,
6
is described.
2
. Results and discussion
We viewed the possibility of accessing the target molecule 1b from either a propargyl
derivative, synthon 3, or from an iodoalkene, synthon 4, in accordance with the
retrosynthetic analysis outlined in Scheme 2.
The synthetic sequence employed to obtain synthons 3 and 4 is depicted in
Scheme 3. The synthesis began with propargylic alcohol, which was the common
starting material for the preparation of intermediates 5 and 6. Thus, in accordance
with well-established procedures, the corresponding tetrahydropyranyl (THP)
ꢀ
derivative was obtained in 71% yield, as a liquid (85–87 C/19 mm) (Henbest,
ꢀ
Jones, & Walls, 1950; 47–50 C/3.5–5 mm), which on treatment with methylmagne-
sium chloride, followed by the addition of methyl chloroformate, gave the
corresponding ester (80% yield), which was purified by low-pressure distillation,
ꢀ
b.p. 114 C/5, 0 mm (Earl & Townsend, 1981; Henbest et al., 1950; Jung & Hagenah,
ꢀ
1
987; 145–148 C/32 mm). Removal of the protective group (Miyashita, Yoshikoshi,
&
Grieco, 1977) provided compound 5, which was treated with monohydrated
lithium iodide in glacial acetic acid and dry acetonitrile without further purification
Ma, Lu, & Li, 1992) to afford diastereoselectively allylic alcohol 6, in 54% yield.
(
The spectroscopic information obtained from 6 was similar to that reported in the
literature (Shinada & Yoshihara, 1996).

1
276
R. Jime´nez et al.
O
O
O
O
MeO
3
OH
O
Me
O
O
O
HO
1
b
O
I
O
4
OM e
Scheme 2. Retrosynthetic analysis of 1b from either synthon 3 or 4.
O
H
1
. DHP, PPTS
CH2Cl2
. MeMgCl, THF, then
ClCO Et
O
I
MeO
LiI.H O, AcOH
MeCN, reflux
2
2
OH
MeO
OH
2
0
OH
3
. EtOH, PPTS, 60 C
6
5
O
O
O
OH
Benzene
reflux
7
Benzene
reflux
O
7
O
O
O
O
O
O
I
O
MeO
4
3
H
MeO
O
Scheme 3. Synthesis of synthons 3 and 4.
The propanoyl Meldrum’s acid derivative (7), required for the next step, was
obtained by the condensation of Meldrum’s acid with propanoic acid in the presence
of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) (Tabuchi,
Hamamoto, Miki, Tejima, & Ichihara, 1994). Alcohol 5 was dissolved in dry benzene

Natural Product Research
1277
ꢀ
and heated with derivative (7) at 80 C for 20 h, in an adaptation of a related protocol
Oikawa, Sugano, & Yonemitsu, 1978). After the work-up procedure, the crude
mixture was purified by column chromatography to deliver 3 as colourless oil, in
0% yield. In the IR spectrum, 3 showed the enol tautomer at 3425, the triple bond
(
6
–
1
1
at 2252 and the carbonyls at 1757.8 and 1721.1 cm . On the one hand, the H NMR
spectrum of 3 showed the methylene protons adjacent to the oxygen and the triple
bond as a singlet at ꢀ 4.86, as well as the methoxy group as a singlet at ꢀ 3.79. On the
other hand, the methylene protons amidst both carbonyls gave a singlet at ꢀ 3.52.
The ethyl group gave a quartet at ꢀ 2.59 (J ¼ 7.24 Hz) and a triplet at ꢀ 1.09
(
J ¼ 7.25 Hz). Likewise, compound 4 was obtained from the reaction of 6 with
Meldrum’s acid derivative (7) and was isolated as a semisolid in 90% yield. In the IR
spectrum, compound 4 showed three distinctive carbonyl bands at 1747, 1730 and
1
ꢁ
1
1
704 cm . In the H NMR spectrum, product 4 showed the vinylic proton as a
triplet at ꢀ 6.71 (J ¼ 1.76 Hz) due to the interaction with the methylene protons (CH -
2
1
), which gave a doublet at ꢀ 4.91 (J ¼ 1.76 Hz), thus confirming the double bond Z
stereochemistry. The methoxy group resonated as a singlet at ꢀ 3.79 and the
methylene protons amidst both carbonyls gave a singlet at ꢀ 3.56. The ethyl group
gave a quartet at ꢀ 2.61 (J ¼ 7.30 Hz) and a triplet at ꢀ 1.11 (J ¼ 7.20 Hz).
On the treatment of tricarbonyl intermediate 3 with sodium hydride in dry THF
at low temperature (0–5 C) for a period of 8 h, a product was isolated, for which
compound 2 (98% crude yield) was proposed based on spectroscopic data. In the IR
ꢀ
ꢁ
1
spectrum, a lactone carbonyl band was absorbed at 1781 cm , while the ester and
ketone absorptions were superimposed to give an intense, slightly broad absorption
ꢁ
1
1
at 1743 cm . In the H NMR spectrum, the lactone methylene protons were found
as a singlet at 5 ppm, the methoxy group was observed as a singlet at 3.75, while
the methylene protons adjacent to the ester were shown at 3.99 ppm. Lactone 2 was
obtained in excellent yield from 4 as well, via an intramolecular condensation
reaction promoted by sodium hydride in dry THF at room temperature.
Compound 2 was poised for an intramolecular Claisen-type condensation.
Accordingly, after lactone 2 was generated in situ, potassium tert-butoxide (3 molar
equivalents) was added and the reaction was kept for 5 h at reflux temperature
(
(
(
THF). After work up of the reaction mixture, phthalide 1b was isolated in 32% yield
1
Scheme 4). The H NMR spectrum showed compound 1b as a singlet at ꢀ 6.41 ppm
Ar–H), the methylene protons as a singlet at ꢀ 5.18 ppm and the methyl group as
a singlet at ꢀ 2.12. On the other hand, the exchangeable signal with D O at ꢀ 2.43
2
was assigned to the hydroxyl groups at C-5 and C-7. These data are in agreement
with those reported by Solberg (1975).
3
3
. Experimental
.1. General
1
13
IR spectra were recorded on a Nicolet spectrometer. H- and C-NMR spectra
1
were recorded with a Jeol Delta-GSX-270 spectrometer. H-NMR spectra were
recorded at 270.05 MHz (spectral width 2700 Hz, acquisition time 1.52 s, pulse width
4
ꢀ
13
5 , 32 scans, recycle delay 2 s). C NMR spectra were recorded at 67.80 MHz
ꢀ
(spectral width 12224.9 Hz acquisition time 1.34 s, pulse width 30 , 128 scans,
recycle delay 0.8 s). The chemical shifts are referenced to internal (CH ) Si
3
4

1
278
R. Jime´nez et al.
O
O
NaH/THF
rt/8h
NaH/THF
rt/8h
O
4
3
O
MeO
2
t-BuOK/THF
5
5ºC/5h
OH
O
O
Me
HO
Scheme 4. Synthesis of 1b from lactone 2.
1b
1
13
(
ꢀ H ¼ 0, ꢀ C ¼ 0). The HRMS were recorded using a Hewlett–Packard HP-5998A
spectrometer.
0
3
.1.1. 3 -Carbomethoxypropyn-2-yl-3-oxo-pentanoate (3)
Propanoyl Meldrum’s acid derivative (7, 200 mg (1.0 mmol)) and hydroxymethyl
propargylic methyl ester (5, 216 mg (1.5 mmol)) were dissolved in anhydrous
benzene and heated at reflux temperature for 20 h, under a nitrogen atmosphere.
The reaction mixture was cooled to room temperature, the solvent was removed
under vacuum and the residue was purified by column chromatography. The title
ꢁ
2
compound was isolated as oil in 60% yield. IR (film), (cm ) 3425, 2252, 1757.8,
1
1
721.1, 1434.7. H NMR (CDCl ), ꢀ 4.86 (s, 2H, H C–O), 3.79 (s, 3H, H C–O),
3 2 3
3
H C). C NMR (CDCl ), ꢀ (ppm). 202.3, 166.2, 153.1, 80.5, 78.0, 52.8, 51.9, 48.3,
.52 (s, 2H, H C(CO) ), 2.60 (q, 2H, J ¼ 7.24 Hz, H C–CO), 1.09 (t, 3H, J ¼ 7.25 Hz,
2
2
2
1
3
3
3
3
6.3, 7.4. HRMS Calcd for C H O : 212.0785; found: 212.0780.
10 12 5
3
.1.2. (Z) 3-Carbomethoxy-2-iodopropen-2-yl-3-oxo-pentanoate (4)
The title compound was isolated as a semisolid in 90% yield after column
chromatography purification, following the same procedure described for the
ꢁ
2
preparation of 3. IR (film), (cm ) 3044.2, 2932.4, 1747.5, 1730.4, 1704.5, 1658.9,
1
1
640.8, 1434.1, 1407.2, 1362.2, 1318.7,1173.3. H NMR (CDCl ), ꢀ 6.72 (t, 1H,
3
J ¼ 1.76 Hz, HC¼C), 4.91 (d, 2H, J ¼ 1.76 Hz, H C–O), 3.79 (s, 3H, H C–O), 3.56
2
3
(
s, 2H, H C(CO) ), 2.61 (q, 2H, J ¼ 7.3 Hz, H C–CO), 1.11 (t, 3H, J ¼ 7.3 Hz, H C).
2
2
2
3
1
3
C NMR (CDCl ) ꢀ 202.5, 165.7, 164.4, 124.7, 110.8, 72.4, 51.8, 48.4, 36.5, 7.5.
3
HRMS Calcd for C H IO : 339.9916; found: 339.9908.
1
0
13
5
3
.1.3. (5H)-3-Propionyl-4-methoxycarbonylmethylfuran-2-one (2)
Sodium hydride (2 molar equivalents) was placed in a flask and washed with dry
hexane (3 ꢂ 5 mL) under argon atmosphere. Freshly distilled dry THF was added

Natural Product Research
1279
ꢀ
and the suspension was cooled to 0–2 C. Compound 3 (1 molar equivalent) dissolved
in dry THF was slowly added to the previous suspension for a period of 15 min.
Stirring was continued until the starting material disappeared (8 h, determined by
TLC, EtOAc : Hexane, 4 : 6). Then, 20% aqueous HCl was added until pH was equal
to 1. The solvent was removed under vacuum and the residue was taken in EtOAc,
and then washed with brine (3 ꢂ 10 mL). The organic extract was dried (Na SO )
2
4
and the solvent was distilled under reduced pressure to yield the title compound as
ꢁ
2)
1
a semisolid in 98% yield. IR (film) (cm 1782, 1743, 1697, 1655. H NMR (CDCl )
3
ꢀ
5.0 (s, 2H, H C–O), 3.98 (s, 2H, H C–CO Me), 3.75 (s, 3H, H C–O), 3.03(q, 2H,
2 2 2 3
J ¼ 7.12 Hz, H C–CO), 1.08(t, 3H, J ¼ 7.12 Hz, H C–CH ). HRMS Calcd for
2
3
2
C H O : 212.0785; found: 212.0778.
1
0
12
5
3
.1.4. 5,7-Dihydroxy-6-methylphthalide (1b)
Under an inert, argon atmosphere, 2 molar equivalents of sodium hydride
(previously washed with dry hexane) was suspended in dry THF. The suspension
ꢀ
was cooled to 2 C and then a dry solution of 3 (1 molar equivalent) in THF was
added for 15 min. Stirring at the same temperature was continued and after 8 h,
TLC (EtOAc : Hexano, 4 : 6) indicated the presence of lactone 2. At this point, freshly
prepared potassium tert-butoxide (3 molar equivalents) in dry THF was slowly
added for 15 min. Then the reaction mixture was refluxed for 5 h. The reaction was
cooled to room temperature and the pH was adjusted to 1 by the addition of 20%
HCl. The solvent was removed under vacuum and the residue was extracted with
ethyl acetate (3 ꢂ 20 mL). The organic extracts were combined, washed with brine
and dried (Na SO ). The solvent was removed under pressure and the residue
2
4
was purified by column chromatography, followed by preparative thin layer
1
chromatography, to give 1b in 31.2% yield. H NMR (CDCl –CD OD) ꢀ 6.41
3
3
(
(
ꢀ
s, 1H, H–Ar), 5.18 (s, 2H, H C–O), 2.12 (s, 3H, H C–Ar), 2.43 (bs, HO–Ar, D O)
2
3
2
3
1
13
lit. H NMR 100 MHz (CD CN-d ) 6.50, 5.16 and 2.04). C NMR (CDCl3),
3
3
164.9, 147.7, 112.4, 103.7, 101.1, 71.1, 7.9.
4
. Conclusion
The key intermediate for the synthesis of dihydroxy-6-methylphthalide (1b) was
compound 2, a 3,4-disubstituted lactone, which in turn became easily accessible from
triple and double bond intermediates, synthons 3 and 4, respectively. The synthetic
approach described here represents the first synthesis of 5,7-dihydroxy-6-
methylphthalide.
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