Total synthesis and confirmation of the absolute stereochemistry of semiviriditoxin, a naphthopyranone metabolite from the fungus Paecilomyces variotii

Article abstract of DOI:10.1016/j.tet.2009.03.016

The first total synthesis of (S)-semiviriditoxin 2 is described. The approach utilizes a tandem Michael-Dieckmann reaction between ortho-toluate 5 and dihydropyran-2-one 6 to construct the naphthopyranone core, the dihydropyran-2-one 6 being prepared from (R)-1,2-epoxy-4-butanol. Spectroscopic comparison of synthetic (S)-semiviriditoxin 2 with (R)-semivioxanthin 3, prepared in four steps from (R)-propylene oxide, confirmed the (S)-stereochemistry of natural semiviriditoxin from Paecilomyces variotii. Crown Copyright

Full text of DOI:10.1016/j.tet.2009.03.016

Tetrahedron 65 (2009) 4007–4012
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis and confirmation of the absolute stereochemistry of
semiviriditoxin, a naphthopyranone metabolite from the fungus
Paecilomyces variotii
Nichole P.H. Tan a b, Christopher D. Donner a
,
,b,
*
a
School of Chemistry, The University of Melbourne, Victoria 3010, Australia
Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of (S)-semiviriditoxin 2 is described. The approach utilizes a tandem Michael–
Dieckmann reaction between ortho-toluate 5 and dihydropyran-2-one 6 to construct the naphthopyr-
anone core, the dihydropyran-2-one 6 being prepared from (R)-1,2-epoxy-4-butanol. Spectroscopic
comparison of synthetic (S)-semiviriditoxin 2 with (R)-semivioxanthin 3, prepared in four steps from (R)-
propylene oxide, confirmed the (S)-stereochemistry of natural semiviriditoxin from Paecilomyces variotii.
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Received 30 November 2008
Received in revised form 16 February 2009
Accepted 6 March 2009
Available online 11 March 2009
1. Introduction
synthesis of the potential precursor semiviriditoxin 2, a natural
product that itself has yet to be the subject of total synthesis. A
The increasing occurrence of bacterial resistance to antibiotics,
and its consequences for human health, necessitates the de-
velopment of new antibiotics that possess novel modes of action.
The bacterial proteinFtsZ, a tubulin-like GTPase, has an essential role
in bacterial cell division wherein it undergoes self-polymerization,
thus initiating the complex process of septation. The high degree of
similarity of FtsZ amongst bacterial species makes it an excellent
concise method for the preparation of naphthopyranones utilizes
the tandem Michael–Dieckmann reaction of ortho-toluates with
4-alkoxypyran-2-ones, a method first reported by Staunton and
7
8
co-workers. Such an approach has been used in both racemic
9
and enantioselective syntheses of semivioxanthin 3. We have
used this methodology towards the synthesis of the talar-
10
oderxines and as the key step in the preparation of pyr-
1
11
target for antibiotic drugs. Viriditoxin 1 has been shown to block
anonaphthoquinones. Herein we report the application of this
FtsZ polymerization with an IC50 of 8.2
spectrum antibiotic activity against Gram-positive pathogens,
m
g/mL, and possesses broad-
method to both the first total synthesis of (S)-semiviriditoxin 2
and a concise synthesis of (R)-semivioxanthin 3, allowing the
absolute stereochemistry of natural semiviriditoxin 2 to be firmly
established.
including methicillin-resistant Staphylococcus aureus and vanco-
2
mycin-resistant Enterococci. First isolated in 1971 from Aspergillus
viridinutans the structure of viriditoxin was originally incorrectly
3
4
assigned, and has since been revised to the structure 1. Whilst the
chirality of the biaryl axis in 1 was established from the circular di-
OH OH
O
O
0
OH OH O
chroism (CD) spectrum, the stereochemistry at C3 and C3 in vir-
O
iditoxin is notknown. Semiviriditoxin 2, the monomeric subunitof 1,
has been obtained from the fungus Paecilomyces variotii. The sim-
O
3
CO Me
5
2
MeO
MeO
CO Me
2
MeO
ilarity of the CD spectrum of 2 with that of (R)-semivioxanthin 3 led
to the proposal of (S)-stereochemistry for semiviriditoxin 2. The
closely related dimeric naphthopyranone asteromine 4 has been
CO Me
3'
2
2
O
6
OH OH
OH OMe O
isolated from a strain of Mycosphaerella asteroma, however, 4 ex-
1
hibits only weak antibacterial and antifungal activities.
In order to ultimately solve the outstanding stereochemical
details of viriditoxin 1, we sought to undertake a stereospecific
O
O
CO H
2
MeO
MeO
OH OH
O
CO H
2
O
*
Corresponding author. Tel.: þ61 3 8344 2411; fax: þ61 3 9347 8189.
E-mail address: cdonner@unimelb.edu.au (C.D. Donner).
MeO
Me
OH OMe O
4
3
0
040-4020/$ – see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.016

4008
N.P.H. Tan, C.D. Donner / Tetrahedron 65 (2009) 4007–4012
2
. Results and discussion
The symmetrical nature of viriditoxin 1 would logically suggest
NMR spectrum of 11 shows signals consistent with the assigned
structure, including three aromatic signals at 6.47 (d, J 2.2 Hz),
6.58 (d, J 2.2 Hz), and 6.85 (s) and a chelated phenolic proton signal
at 13.14. The naphthopyranone 11 contains the complete carbon
framework found in semiviriditoxin 2, only requiring seemingly
trivial functional group manipulations for its ultimate conversion
to 2.
The silyl group in 11 was removed by exposure to aq HCl/THF to
deliver the primary alcohol 12 in 70% yield after recrystallization.
The analytical and spectroscopic data (Experimental) were in
complete accord with structure 12. The primary alcohol 12 was
then converted to the corresponding methyl ester 13 by sequential
d
the potential for synthesis via oxidative phenolic coupling of the
corresponding monomer semiviriditoxin 2 (Scheme 1). The full
carbon framework of 2 should be amenable to rapid construction
utilizing a tandem Michael–Dieckmann reaction between the or-
tho-toluate 5 and lactone 6. In turn, lactone 6 should be available
from the terminal epoxide 7, which itself is available from (S)-
aspartic acid.12
d
OH OH
O
oxidation (TEMPO/PhI(OAc) then NaClO
2
2
) followed by esterifica-
O
tion (MeOH, concd H SO ) to give semiviriditoxin-9-O-methyl
2
4
1
CO Me
ether 13 in 84% yield for the three steps. As anticipated, the spec-
2
MeO
5
troscopic data for 13 were very similar to that reported for semi-
2
1
viriditoxin 2. Notably, the H NMR spectrum of 13 differs only by
OMe
O
the presence of an extra methoxy signal (
weakly chelated proton signal ( 9.44) seen in the spectrum of 2.
Final conversion of 13 to semiviriditoxin 2 requires selective
demethylation of the C9 methyl ether. The use of BCl gave the best
d 3.98), replacing the
CO Me
2
O
O
d
+
OH
MeO
Me
MeO
OTBS
7
3
5
6
results for this conversion, the reaction being stopped before
complete conversion to ensure that disruption of the C7 methyl
ether was avoided. After separation from unreacted 13, (S)-semi-
Scheme 1.
Firstly, (S)-aspartic acid 8 was converted to the epoxyalcohol 7 in
5% yield over three steps following the method of Volkmann and
ꢁ
5
viriditoxin 2 was obtained as a colourless solid, mp 169–171 C (lit.
8
ꢁ
1
13
1
2
mp 168–170 C), with both the H and C NMR spectra for the
synthetic material being virtually identical to the reported data for
co-workers (Scheme 2). Silylation of the alcohol 7 proceeded ef-
ficiently to give the protected (R)-epoxide 9, the spectroscopic data
of which (see Experimental) were in good agreement with that
reported for the same material prepared from (S)-malic acid. The
epoxide 9 was then treated with the anion of methyl propiolate
under the Yamaguchi–Hirao conditions to deliver the acetylene
0 in 72% yield. Exposure of the acetylene 10 to sodium methoxide
0.3 equiv) in methanol leads to conjugate addition and sub-
5
the natural product. Significantly, the specific rotation for (S)-
semiviriditoxin 2 prepared in this way, [
closely matches the reported value for semiviriditoxin, [
2
3
13
a
]
ꢀ8.60 (c 0.06, CHCl ),
D
3
20
a
]
D
ꢀ9.0 (c
5
1
4
0.21, CHCl3), and on this basis the previously proposed (S)-ste-
reochemistry for semiviriditoxin 2 from P. variotii can be verified.
Although the similarity in specific rotation values between
synthetic 2 and that reported for the naturally occurring material
seemed to confirm the (S)-stereochemistry of natural semi-
viriditoxin 2, we thought it prudent to corroborate this conclusion.
Previously, the (S)-stereochemistry of semiviriditoxin from P. vari-
1
(
1
5
sequent lactonization to give the pyranone 6 in 80% yield. The initial
adduct formed between 10 and methanol would presumably be
16
formed as a mixture of isomers, however, under the reaction
conditions equilibration between the E/Z isomers can occur. Ulti-
mately, all the E-isomer is trapped as the lactone 6 and no
uncyclized material was observed. With the key stereochemically
defined lactone fragment in hand, we could then proceed with the
tandem Michael–Dieckmann reaction.
5
otii was proposed based on the similarity of the CD spectrum of 2
with the reported CD data for (R)-semivioxanthin 3 from Penicillium
18,19
citreo-viride.
Given that the CD data for semiviriditoxin 2 and
semivioxanthin 3 were obtained in different solvents, we felt that
direct comparison of these materials under similar conditions
would be warranted in order to confirm the legitimacy, in this case,
of assigning the stereochemistry in this manner.
We have recently investigated the scope of the tandem Michael–
Dieckmann reaction between oxygenated ortho-toluates and 4-
methoxypyran-2-ones.17 Fortuitously in the present context, the
To obtain (R)-semivioxanthin 3 we undertook the concise syn-
thesis outlined in Scheme 3. The approach closely parallels that of
toluate 5 is amenable to reaction with the lactone 6. Thus, depro-
ꢁ
tonation of the toluate 5 with LDA at ꢀ65 C followed by addition of
9
1
Drochner and M u¨ ller for their synthesis of (R)-semivioxanthin. In
lactone 6 delivers the naphthopyranone 11 in 36% yield. The
H
CO Me
2
O
NH2
O
a
c
d
O
CO H
OR
2
HO C
2
OH
OTBS
MeO
OTBS
8
7 R = H
R = TBS
b
6
9
10
OR OH
O
O
OMe
O
OMe OH
O
CO Me
g
2
e
O
O
+
CO Me
2
MeO
Me
MeO
OTBS
MeO
OR
MeO
5
6
11 R = TBS
2 R = H
13 R = Me
R = H
f
h
1
2
ꢁ
S, THF, ꢀ30 ꢁC to rt, 18 h (97%); (iii) K
Scheme 2. Reagents and conditions: (a) (i) NaNO
CH Cl
, 4 h (98%); (c) methyl propiolate, nBuLi, BF
g) (i) PhI(OAc) , TEMPO, CH Cl , 20 h; (ii) NaClO
2
, H
$Et
2
SO
4
, KBr, H
2
O, 0 C, 4 h (91%); (ii) BH
3
$Me
2
2
ꢁ
CO
3
, CH Cl , 72 h (96%); (b) TBSCl, imidazole,
2
2
ꢁ
2
2
3
2
O, THF, ꢀ78 C, 30 min (72%); (d) NaOMe, MeOH, 16 h (80%); (e) LDA, THF, ꢀ60 C, 30 min (36%); (f) THF, 10% HCl, 16 h (70%);
t
(
2
2
2
2
,
BuOH, H
2
O, NaH
2
PO
4
, 3 h; (iii) MeOH, concd H
SO
2 4
, 16 h (84%, three steps); (h) BCl
3
, CH
2
Cl
2
, 6 h (75%).

N.P.H. Tan, C.D. Donner / Tetrahedron 65 (2009) 4007–4012
4009
this previously reported synthesis of 3, the lactone 16 was obtained
in three steps from tert-butyl 3,5-dioxohexanoate using a regio-
and stereoselective (99.4% ee) enzymatic reduction, lactonization,
and O-methylation sequence, whilst a benzyloxymethyl protected
ortho-toluate was employed in the tandem reaction. In the present
work we prepared the (R)-lactone 16 in just two steps from (R)-
propylene oxide 14. Thus, addition of the (R)-epoxide 14 to the
anion of ethyl propiolate gave the acetylene 15 (Scheme 3), which
upon exposure to catalytic sodium methoxide gave the lactone 16
in 66% yield over the two steps. In the present case we chose to use
the methoxyethoxymethyl (MEM) protected toluate 17 for the
tandem Michael–Dieckmann reaction with (R)-lactone 16, de-
livering the naphthopyranone 18 in 39% yield. Final deprotection of
plates (Merck 60GF254) and compounds were visualized at 254 nm
and 365 nm or stained with 20% w/w phosphomolybdic acid in
ethanol. Flash column chromatography was performed on silica gel
(Kieselgel 60, 230–400 mesh) using the indicated solvent system.
Melting points were measured using a Bausch and Lomb hot-stage
1
13
melting point apparatus and are uncorrected. H and C NMR
spectrawere recorded using a Varian-500 spectrometeroperating at
500 MHz and 125 MHz, respectively. The residual peak of CHCl
3
was
1
used as internal reference (7.26 ppm) for H NMR spectra whilst the
13
3
central peak of CDCl was used as reference (77.0 ppm) for C NMR
1
spectra. Chemical shifts are reported in parts per million (ppm). H
NMR data are reported in the following order: number of protons,
multiplicity, coupling constant (J, Hz), assignment. Infrared (IR)
spectra were recorded on a Perkin–Elmer Spectrum One FT-IR
spectrometer. Low resolution electrospray ionization (ESI) mass
spectra were recorded on a Shimadzu GC/MS-QP505A. High reso-
lution ESI mass spectra were recorded on a Thermo-Finnigan LTQ-FT
ICR hybrid mass spectrometer. Specific rotations were measured at
589 nm using a JASCO DIP-1000 polarimeter using a 1 dm cell with
concentrations quoted in g/100 mL in the solvent cited in each case
18 provided semivioxanthin 3 in 17% yield over the four steps. This
compares favourably with the method of Drochner and M u¨ ller that
produced 3 in 5% yield over five steps. Importantly, the spectro-
scopic data for synthetic (R)-semivioxanthin 3 obtained in this way
were in complete agreement with the reported data for naturally
18
occurring semivioxanthin 3.
ꢀ1
2
ꢀ1
and are given in units 10 deg cm g . Circular dichroism spectra
were obtained using a JASCO J-815 CD spectrometer for solutions in
the solvent specified. Anhydrous tetrahydrofuran (THF) and
dichloromethane were pre-dried over activated alumina under ar-
gon. Ether refers to diethyl ether, while petrol refers to the hydro-
CO2Et
O
O
a
b
O
Me
OH
Me
MeO
Me
O
14
ꢁ
16
carbon fraction boiling in the range 40–60 C. Micro elemental
15
analyses were conducted by Chemical and MicroAnalytical Services
Pty. Ltd., Geelong, Victoria, Australia.
OR OH
MEMO
O
CO Me
2
c
O
3.2. (R)-2-(2-(tert-Butyldimethylsilyloxy)ethyl)oxirane 9
O
+
MeO
Me
MeO
Me
MeO
Me
To the (R)-epoxide 7 (2.4 g, 27.2 mmol) in dichloromethane
(50 mL) were added imidazole (1.95 g, 28.6 mmol) and tert-butyl-
dimethylsilyl chloride (4.31 g, 28.6 mmol) and the mixture was
stirred at ambient temperature for 4 h. Ether (75 mL) was added
and the mixture was washed successively with water, dilute
hydrochloric acid, 10% sodium hydrogen carbonate and brine, then
17
16
18 R = MEM
R = H
d
3
Scheme 3. Reagents and conditions: (a) ethyl propiolate, nBuLi, BF
O, THF, ꢀ90 ꢁC,
3
$Et
2
h (82%); (b) NaOMe, MeOH, 16 h (80%); (c) LDA, THF, ꢀ60 ꢁC, 30 min (39%); (d) THF,
2
concd HCl, 8 h (66%).
With both (S)-semiviriditoxin 2 and (R)-semivioxanthin 3 now
available to us we could undertake their direct spectroscopic
comparison. The CD spectrum of synthetic (S)-semiviriditoxin 2
obtained in trifluoroethanol) exhibited a maximum at 370 nm and
minimum at 262 nm, in close agreement with the reported data for
natural semiviriditoxin (in dioxane), whilst synthetic (R)-semi-
vioxanthin 3 (in trifluoroethanol) exhibited a maximum at 363 nm
and minimum at 266 nm, also in accord with reported data for
natural semivioxanthin (in cyclohexane/5% dioxane). Further-
more, the near identity of the CD spectra for synthetic 2 and 3,
obtained here under similar conditions, supports the previous ap-
plication of this technique for the assignment of the stereochem-
4
dried (MgSO ) and concentrated in vacuo to give the title com-
pound 9 (5.4 g, 98%) as a colourless oil that was used without fur-
24
13
26
ther purification. [
a
]
D
þ11.0 (c 2.00, CHCl
)}; H NMR (CDCl , 500 MHz) 0.06 (6H, s, Si(CH
s, SiC(CH ), 1.67–1.81 (2H, m, CH ), 2.52 (1H, d, J 5.1 and 2.8 Hz, 1-
), 2.78 (1H, m, 1-H ), 3.05 (1H, m, 2-H), 3.78 (2H, t, J 5.8 Hz,
, 125 MHz)
ꢀ5.4, 18.3, 25.9, 35.9, 47.2,
3
) {lit.
[
a
]
D
þ12.5 (c 2.11,
(
1
CHCl
3
3
d
3 2
) ), 0.90 (9H,
3
)
3
2
5
H
CH
a
H
b
a b
H
13
2
OSi); C NMR (CDCl
3
d
50.0, 60.0.
18
3.3. Methyl (S)-7-(tert-butyldimethylsilyloxy)-5-hydroxyhept-
2-ynoate 10
5
istry of semiviriditoxin.
To a solution of methyl propiolate (0.41 g, 4.82 mmol) in THF
In summary, this work constitutes the first total synthesis of the
fungal metabolite (S)-semiviriditoxin 2. Spectroscopic comparison
of synthetic 2 with the reported data for semiviriditoxin 2 and with
synthetic (R)-semivioxanthin 3, prepared in four steps from (R)-
propylene oxide, has confirmed the (S)-stereochemistry of semi-
viriditoxin from P. variotii. At this stage, attempted dimerization of 2
to give viriditoxin 1 has not been successful and investigations into
methods to effect this transformation are ongoing.
ꢁ
(
1
1
5
8 mL) at ꢀ78 C was added n-butyllithium (2.5 M in hexane,
.93 mL, 4.82 mmol) dropwise and the mixture was stirred for
ꢁ
0 min at ꢀ78 C. Boron trifluoride/diethyl etherate (0.65 mL,
.14 mmol) was added and stirring was continued for 10 min. A
solution of (R)-epoxide 9 (0.65 g, 3.21 mmol) in THF (1 mL) was
ꢁ
added and stirring was continued for 30 min at ꢀ78 C. Aqueous
ammonium chloride was added and the mixture was extracted
with ethyl acetate (4ꢂ5 mL), the combined organic extracts washed
4
with brine, dried (MgSO ) and concentrated in vacuo. Flash column
3
3
. Experimental section
chromatography (ethyl acetate/petrol 1:3) afforded the title com-
2
6
pound 10 (0.66 g, 72%) as a colourless oil. [
a
]
D
þ3.10 (c 2.00, CHCl
3
).
þ
þ
.1. General
Found: [MþNa] 309.1492.
C
14
H
26
O
4
SiNa requires [MþNa]
0.09 (6H, s, Si(CH
), 2.51 (1H, dd, J 17.1 and
), 2.60 (1H, dd, J 17.1 and 6.3 Hz, 4-H ), 3.76 (3H, s,
), 3.85 (1H, m, 7-H ), 3.93 (1H, m, 7-H ), 4.08 (1H, m,
1
3
09.1493; H NMR (CDCl
(9H, s, SiC(CH
7.1 Hz, 4-H
OCH
3
, 500 MHz)
) ), 1.75–1.86 (2H, m, 6-H
3 3 2
d
3 2
) ), 0.90
All moisture sensitive reactions were performed under a dry
nitrogen atmosphere in oven-dried or flame-dried glassware. Thin
layer chromatography (TLC) was performed on pre-coated silica
a
H
b
a b
H
H
a b
3
a
H
b

4010
N.P.H. Tan, C.D. Donner / Tetrahedron 65 (2009) 4007–4012
5
5
-H); 13C NMR (CDCl
2.6, 62.2, 69.9, 74.4, 86.2, 154.0;
3
,125 MHz)
d
ꢀ5.64, ꢀ5.60,18.1, 25.8, 27.2, 37.1,
64.54, H 5.60%. Anal. Calcd for C17
H
18
O
6
: C 64.14, H 5.70. Found:
þ
þ
1
n
max 3407, 2931, 2239, 1713, 1436,
[MþH] 319.1176. C17
H
19
O
6
requires [MþH] 319.1176; H NMR
), 2.12 (1H, m, 3-CH ),
OH), 3.91 (3H, s, OCH ), 3.96
), 4.80 (1H, m, 3-H), 6.47 (1H, d,
J 2.4 Hz, ArH), 6.58 (1H, d, J 2.4 Hz, ArH), 6.85 (1H, s, ArH),13.07 (1H,
ꢀ
1
þ
þ
1251, 1073, 835 cm ; m/z (ESI ) 287.2 [MþH] .
(CDCl
3
, 500 MHz)
d
2.01 (1H, m, 3-CH
a
H
b
a b
H
3.02 (2H, m, 4-H
2
), 3.90 (1H, m, CH
a
H
b
3
3
4
.4. (R)-6-(2-(tert-Butyldimethylsilyloxy)ethyl)-5,6-dihydro-
-methoxy-2H-pyran-2-one 6
(1H, m, CH OH), 3.99 (3H, s, OCH
a
H
b
3
13
s, 10-OH); C NMR (CDCl
76.8, 98.3, 98.9, 100.7, 110.6, 115.4, 134.2, 141.5, 160.6, 161.8, 164.1,
170.9; max 3412, 2947, 1632, 1606, 1583, 1371, 1340, 1171, 1112,
3
, 125 Hz) d 33.6, 37.4, 55.4, 56.2, 58.6,
To a solution of the acetylene 10 (0.96 g, 3.35 mmol) in metha-
ꢁ
nol (20 mL) at 0 C was added sodium methoxide (0.70 M in
methanol, 1.44 mL) dropwise. The mixture was stirred at 0 C for
n
ꢁ
ꢀ1
þ
þ
787 cm ; m/z (ESI ) 319.1 [MþH] .
1
h and then at ambient temperature for 16 h. The mixture was
diluted with saturated ammonium chloride and extracted with
ethyl acetate (4ꢂ10 mL), dried (MgSO ) and concentrated in vacuo.
Flash column chromatography (ethyl acetate/petrol 1:2) afforded
3.7. (S)-3,4-Dihydro-10-hydroxy-7,9-dimethoxy-1H-
naphtho[2,3-c]pyran-1-one-3-acetic acid methyl ester 13
4
2
6
the title compound 6 (765 mg, 80%) as a colourless oil. [
a]
D
ꢀ46.7
To alcohol 12 (220 mg, 0.69 mmol) in dichloromethane (7 mL)
were added [bis(acetoxy)iodo]benzene (267 mg, 0.83 mmol) and
TEMPO (11 mg, 0.07 mmol) and the mixture was stirred at ambient
temperature for 16 h. The reaction mixture was then diluted with
aq sodium thiosulfate (10 mL) and extracted with chloroform
þ
(c 2.00, CHCl
3
). Found: [MþNa] 309.1493. C14
H
26
O
4
SiNa requires
0.04 (6H, s,
), 1.97 (1H, m,
þ
1
[MþNa] 309.1493; H NMR (CDCl
3
, 500 MHz)
d
Si(CH
-CH
2.0 and 1.4 Hz, 5-Hax), 3.73 (3H, s, OCH
.81 (1H, m, CH OSi), 4.56 (1H, m, 6-H), 5.13 (1H, d, 1.4 Hz, 3-H);
3
)
2
), 0.87 (9H, s, SiC(CH
3
)
3
), 1.83 (1H, m, 6-CH
a
H
b
6
1
a
H
b
), 2.37 (1H, dd, J 17.1 and 3.7 Hz, 5-Heq), 2.53 (1H, dd, J 17.1,
), 3.76 (1H, m, CH OSi),
3
a
H
b
(4ꢂ5 mL). The combined organic layers were dried (MgSO
4
) and
3
a
H
b
concentrated in vacuo to give an oily residue. The residue, con-
taining the crude intermediate aldehyde, was dissolved in a mix-
ture of acetone (3 mL), tert-butanol (5 mL) and water (2 mL).
2-Methyl-2-butene (1 mL) was added followed by sodium dihy-
drogenphosphate (323 mg) and sodium chlorite (125 mg,
1.38 mmol) and the mixture was stirred vigorously for 3 h. After
addition of 2 M hydrochloric acid (2 mL) the mixture was extracted
with chloroform (6ꢂ5 mL) and the combined organic layers were
1
3
C NMR (CDCl
3
, 125 MHz)
d
ꢀ5.5, ꢀ5.4, 18.2, 25.8, 33.2, 37.6, 56.0,
5
8
8.5, 73.1, 90.3, 167.3, 172.9;
40, 776 cm ; m/z (ESI ) 287.2 [MþH] .
n
max 2929, 1710, 1625, 1251, 1220, 1090,
ꢀ1
þ
þ
3
.5. (S)-3,4-Dihydro-10-hydroxy-3-(2-(tert-butyldimethyl-
silyloxy)ethyl)-7,9-dimethoxy-1H-naphtho[2,3-c]pyran-1-one 11
To a solution of diisopropylamine (0.60 mL, 4.28 mmol) in THF
4
dried (MgSO ) and concentrated in vacuo. The resultant crude acid
ꢁ
(
2
15 mL) at ꢀ60 C was added n-butyllithium (1.6 M in hexane,
was dissolved in methanol (10 mL) with concentrated sulfuric acid
(0.05 mL) and the solution was stirred at ambient temperature for
16 h. After concentration of the mixture in vacuo, water (10 mL)
was added and the mixture was extracted with chloroform
.7 mL, 4.28 mmol). The reaction mixture was allowed to warm to
ꢁ
ꢁ
ꢀ
10 C and stirred for 15 min. After cooling to ꢀ70 C, methyl 2,4-
dimethoxy-6-methylbenzoate
5
(450 mg, 2.14 mmol) in THF
(
2 mL) was added and stirring was continued for 10 min at
70 C. To the resultant red solution was added the (R)-lactone 6
(4ꢂ5 mL) and the combined organic layers were dried (MgSO
4
) and
ꢁ
ꢀ
concentrated in vacuo. Flash column chromatography (ethyl ace-
(
612 mg, 2.14 mmol) in THF (2 mL) and the mixture was allowed
tate/petrol 2:1) afforded the title compound 13 (200 mg, 84%, three
ꢁ
18
to warm to 0 C over 30 min. The reaction was quenched with
saturated ammonium chloride (10 mL), extracted with ethyl ace-
tate (3ꢂ10 mL) and the combined organic layers were washed
steps from 12) as a pale yellow oil. [
a
O
d
]
D
ꢀ20.2 (c 1.14, CHCl
3
).
þ
þ
Found: [MþNa]
369.0944.
C
18
H
18
7
Na requires [MþNa]
1
369.0945; H NMR (CDCl
6.8 Hz, 3-CH
dd, J 15.9 and 10.6 Hz, 4-Hax), 3.10 (1H, dd, J 15.9 and 3.4 Hz, 4-Heq),
3.74 (3H, s, OCH ), 3.90 (3H, s, OCH ), 3.98 (3H, s, OCH ), 5.01 (1H,
m, 3-H), 6.46 (1H, d, J 2.2 Hz, ArH), 6.56 (1H, d, J 2.2 Hz, ArH), 6.85
3
, 500 MHz)
2.74 (1H, dd, J 16.2 and
with brine, dried (MgSO
4
) and concentrated in vacuo. Repeated
a
H
b
), 2.95 (1H, dd, J 16.2 and 6.4 Hz, 3-CH
a
H
b
), 3.02 (1H,
flash column chromatography (ethyl acetate/petrol 1:4 then
dichloromethane/ethyl acetate 19:1) afforded the title compound
1
3
3
3
2
2
1 (330 mg, 36%) as an oil. [
a
]
D
þ10.2 (c 0.16, CH
2 2
Cl ). Found:
þ
þ
1
13
[
MþNa] 455.1862. C23
32
H O
6
SiNa requires [MþNa] 455.1860; H
(1H, s, ArH), 12.96 (1H, s, 10-OH); C NMR (CDCl
39.4, 52.1, 55.5, 56.2, 75.0, 98.5, 99.0, 100.5, 110.7, 115.6, 133.4, 141.5,
160.7, 161.9, 164.2, 170.0, 170.3; max 2931, 1740, 1634, 1609, 1375,
1209, 1165, 1112, 750 cm ; m/z (ESI ) 347.1 [MþH] .
3
, 125 MHz) d 33.0,
NMR (CDCl
3
, 500 MHz)
d
0.07 (6H, s, Si(CH
3
)
2
), 0.89 (9H, s,
), 2.07 (1H, m, 3-CH ), 3.01 (2H,
OSi), 3.88 (1H, m, CH OSi), 3.91
), 4.75 (1H, m, 3-H), 6.47 (1H, d, J
.2 Hz, ArH), 6.58 (1H, d, J 2.2 Hz, ArH), 6.85 (1H, s, ArH), 13.14
SiC(CH
m, 4-H
(
3
)
3
), 1.94 (1H, m, 3-CH
a
H
b
a
H
b
n
ꢀ
1
þ
þ
2
), 3.82 (1H, m, CH
3H, s, OCH
a
H
b
a
H
b
3
), 3.99 (3H, s, OCH
3
2
(
3.8. (S)-3,4-Dihydro-9,10-dihydroxy-7-methoxy-1H-
naphtho[2,3-c]pyran-1-one-3-acetic acid methyl ester [(S)-
semiviriditoxin] 2
1H, s, 10-OH); 1 C NMR (CDCl
3
, 125 MHz)
5.9, 33.6, 37.8, 55.4, 56.2, 58.6, 76.5, 98.3, 98.9, 100.9, 110.7, 115.3,
max 3401, 2948, 1719, 1632,
d
ꢀ5.42, ꢀ5.40, 18.2,
3
2
1
1
(
34.5, 141.5, 160.6, 161.7, 164.0, 171.0;
n
ꢀ
1
608, 1583, 1375, 1254, 1208, 1164, 1110, 1050, 829 cm ; m/z
To ester 13 (24 mg, 0.069 mmol) in dichloromethane (2 mL) at
0 C was added boron trichloride (0.55 mL, 0.55 mmol). The mix-
ꢀ
ꢀ
ꢁ
ESI ) 317.1 [MꢀTBS] .
ture was allowed to warm to ambient temperature and stirred for
a further 6 h. Water (3 mL) was added and the mixture was stirred
vigorously for 30 min before being extracted with dichloromethane
3
.6. (S)-3,4-Dihydro-10-hydroxy-3-(2-hydroxyethyl)-7,9-
dimethoxy-1H-naphtho[2,3-c]pyran-1-one 12
(
3ꢂ5 mL). The combined organic layers were dried (MgSO
4
) and
To the silyl ether 11 (1.54 g, 3.66 mmol) in THF (60 mL) was
added 10% hydrochloric acid (40 mL). After stirring overnight, the
mixture was concentrated in vacuo. The residue was diluted with
concentrated in vacuo. Purification by flash column chromatogra-
phy (chloroform/ethyl acetate/formic acid, 50:1:0.1) afforded
unreacted methyl ether 13 (6 mg, 25%) and (S)-semiviriditoxin 2
(13 mg, 57%; 75% based on recovered 13) as colourless crystals, mp
H
2
O (10 mL) and extracted with ethyl acetate (3ꢂ15 mL). The
combined organic layers were washed with H O (10 mL), dried
MgSO ) and concentrated in vacuo. The crude solid was recrys-
tallized from acetone to afford 12 (0.490 g, 70%) as colourless
ꢁ
5
ꢁ
23
5
2
169–171 C (lit. mp 168–170 C). [
a
]
D
ꢀ8.60 (c 0.06, CHCl
3
) {lit.
2
0
(
4
[a
]
D
ꢀ9.0 (c 0.21, CHCl
3
)}; CD (trifluoroethanol) 217 (D3 ꢀ6.2), 237
þ
(þ0.5), 262 (ꢀ4.8), 320 (þ0.5), 370 nm (þ1.2). Found: [MþNa]
ꢁ
19
Na requires [MþNa]þ 355.0788; H NMR (CDCl
1
needles, mp 163–164 C. [
a
]
D
þ7.16 (c 0.25, acetone). Found: C
355.0788. C17
H
16
O
7
3
,

N.P.H. Tan, C.D. Donner / Tetrahedron 65 (2009) 4007–4012
4011
5
1
H
00 MHz)
6.4 and 6.6 Hz, 3-CH
ax), 3.14 (1H, ddd, J 16.0, 3.4 and 0.8 Hz, 4-Heq), 3.76 (3H, s,
CO CH ), 3.89 (3H, s, 7-OCH ), 5.06 (1H, m, 3-H), 6.55 (1H, d, J
.2 Hz, 8-H), 6.59 (1H, d, J 2.2 Hz, 6-H), 6.91 (1H, br s, 5-H), 9.44 (1H,
d
2.78 (1H, dd, J 16.4 and 6.6 Hz, 3-CH
a
H
b
), 2.98 (1H, dd, J
quenched with saturated ammonium chloride (10 mL), extracted
a
H
b
), 3.05 (1H, ddd, J 16.0, 10.8 and 1.4 Hz, 4-
with ethyl acetate (3ꢂ10 mL) and the combined organic layers were
4
washed with brine, dried (MgSO ) and concentrated in vacuo. Flash
2
3
3
column chromatography (ethyl acetate/petrol 1:2) afforded the ti-
ꢁ
2
tle compound 18 (160 mg, 39%) as colourless needles, mp 93–94 C.
13
21
þ
s, 9-OH), 13.59 (1H, s, 10-OH); C NMR (CDCl
9.4, 52.2, 55.5, 75.8, 99.0, 99.6, 101.7, 108.4, 116.3, 132.2, 140.6,
58.6, 162.8, 163.1, 169.8, 170.7; max 3329, 2930, 2852, 1738, 1649,
3
, 125 MHz)
d
32.6,
[
a
]
D
ꢀ3.45 (c 0.82, CHCl
3
). Found: [MþNa] 385.1258. C19
22
H O
7
Na
1.53 (3H,
), 3.61 (2H, m,
), 4.71 (1H, m, 3-H), 5.43
O), 6.65 (1H, d, J 2.3 Hz, ArH), 6.77 (1H, d, J 2.3 Hz, ArH),
þ
1
3
1
requires [MþNa] 385.1258; H NMR (CDCl
3
, 500 MHz) d
n
d, J 6.3, 3-CH
CH ), 3.89 (3H, s, 7-OCH
(2H, s, OCH
3
), 2.97 (2H, m, 4-H
2 3
), 3.39 (3H, s, OCH
ꢀ1
þ
þ
1
1
627, 1582, 1160, 750 cm ; m/z (ESI ) 333.1 [MþH] . The H and
2
3
), 3.96 (2H, m, CH
2
1
3
5
C NMR data were in agreement with the literature.
2
13
6
.85 (1H, s, ArH), 13.05 (1H, s, 10-OH); C NMR (CDCl
20.6, 34.9, 55.3, 58.9, 68.1, 71.5, 75.6, 94.5, 100.6,100.7,103.2,111.2,
15.2, 134.0, 141.2, 157.5, 161.4, 163.9, 171.1; max 2919, 1652, 1610,
1582, 1387, 1261, 1168, 1149, 1125, 1092, 1049, 1023, 938, 845 cm
3
, 125 MHz)
3
.9. Ethyl (R)-5-hydroxyhex-2-ynoate 15
d
1
n
ꢀ
1
To a solution of ethyl propiolate (0.63 g, 6.42 mmol) in THF
;
ꢁ
þ
þ
(
4
10 mL) at ꢀ90 C was added n-butyllithium (1.6 M in hexane,
m/z (ESI ) 363.2 [MþH] .
.0 mL, 6.42 mmol) and the mixture was stirred for 30 min at
ꢁ
ꢀ
90 C. Boron trifluoride/diethyl etherate (0.82 mL, 6.42 mmol)
3.12. (R)-3,4-Dihydro-9,10-dihydroxy-7-methoxy-3-methyl-
1H-naphtho[2,3-c]pyran-1-one [(R)-semivioxanthin] 3
was added followed by a solution of (R)-propylene oxide 14 (0.25 g,
4
.30 mmol) in THF (2 mL) and stirring was continued for 2 h at
90 C. Saturated ammonium chloride was added and the mixture
ꢁ
ꢀ
To the methoxyethoxymethyl ether 18 (16 mg, 0.044 mmol) in
THF (1 mL) was added concentrated hydrochloric acid (0.05 mL)
and the solution was stirred at ambient temperature for 8 h. After
diluting with chloroform (4 mL) and ethyl acetate (2 mL) and stir-
ring for 15 h, water (5 mL) was added and the mixture was
extracted with chloroform (3ꢂ5 mL) and the combined organic
was extracted with diethyl ether (3ꢂ5 mL) and the combined or-
ganic layers washed with brine, dried (MgSO ) and concentrated in
vacuo. Flash column chromatography (ethyl acetate/petrol 1:3)
4
2
4
afforded the title compound 15 (0.55 g, 82%) as a colourless oil. [
a]
D
þ
ꢀ
9.85 (c 3.05, CHCl
3
). Found: [MþNa] 179.0680. C
8
H
12
O
3
Na re-
1.30 (3H, d, J
), 1.99 (1H, br s, OH), 2.49
), 2.53 (1H, dd, J 17.1 and 5.3 Hz, 4-
þ
1
quires [MþNa] 179.0679; H NMR (CDCl
3
, 500 MHz)
d
4
layers dried (MgSO ) and concentrated in vacuo. Flash column
chromatography (chloroform/ethyl acetate/formic acid 95:4:1)
6
.4 Hz, CH
1H, dd, J 17.1 and 6.3 Hz, 4-H
), 4.05 (1H, m, 5-H), 4.22 (2H, q, J 7.1 Hz, CH
CDCl , 125 MHz) 14.0, 22.6, 29.1, 62.0, 65.9, 75.1, 85.5, 153.6;
408, 2978, 2234, 1705, 1251, 1067, 752 cm ; m/z (ESI ) 156.9
3
), 1.31 (3H, t, J 7.1 Hz, CH
2
CH
3
(
H
(
3
a
H
b
afforded (R)-semivioxanthin 3 (8 mg, 66%) as a pale yellow solid,
13
ꢁ
18
ꢁ
a
H
b
2
CH
3
); C NMR
mp 174–177 C (lit. mp 185 C), CD (trifluoroethanol) 216 (D3
ꢀ5.0), 238 (þ0.8), 266 (ꢀ3.1), 323 (þ0.4), 363 nm (þ1.0). Found:
3
d
n
max
ꢀ1
þ
ꢀ
ꢀ
1
[MꢀH] 273.0776. C15
13
H O
5
requires [MꢀH] 273.0769; H NMR
þ
[MþH] .
3 3
(CDCl , 500 MHz) d 1.55 (3H, d, J 6.3, 3-CH ), 2.96 (1H, ddd, J 16.0,
1
0.3 and 1.4 Hz, 4-Hax), 3.02 (1H, ddd, J 16.0, 3.8 and 0.9 Hz, 4-Heq),
3.89 (3H, s, 7-OCH ), 4.76 (1H, m, 3-H), 6.54 (1H, d, J 2.4 Hz, ArH),
6.57 (1H, d, J 2.4 Hz, ArH), 6.88 (1H, br s, ArH), 9.48 (1H, s, 9-OH),
3
.10. (R)-5,6-Dihydro-4-methoxy-6-methyl-2H-pyran-
3
2
-one 16
13
1
3.77 (1H, s, 10-OH); C NMR (CDCl
76.5, 99.2, 99.5, 101.5, 108.3, 116.0, 133.1, 140.5, 158.6, 162.7, 163.0,
171.5; max 3383, 2930, 1637, 1580, 1381, 1323, 1246, 1158, 1121,
1083, 1033, 841 cm ; m/z (ESI ) 273.0 [MꢀH] . The H and
3
, 125 MHz) d 20.8, 34.7, 55.4,
To a solution of the acetylene 15 (300 mg, 1.92 mmol) in
ꢁ
methanol (10 mL) at 0 C was added sodium methoxide (0.72 M in
n
ꢁ
ꢀ1
ꢀ
ꢀ
1
13
methanol, 0.65 mL) dropwise. The mixture was stirred at 0 C for
C
18
1
h and then at ambient temperature for 16 h. The mixture was
diluted with water (15 mL), 2 M hydrochloric acid (1 mL) and
) and concen-
NMR data were in agreement with the literature.
extracted with chloroform (3ꢂ5 mL), dried (MgSO
4
Acknowledgements
trated in vacuo. Flash column chromatography (ethyl acetate/pet-
rol 2:1) afforded the title compound 16 (218 mg, 80%) as
Financial support from the Australian Research Council through
the Centres of Excellence program is gratefully acknowledged.
Professor Carl Schiesser, The University of Melbourne, is acknowl-
edged for useful discussions.
ꢁ
9
ꢁ
24
a colourless solid, mp 58–59 C (lit. mp 61 C). [
a
]
D
ꢀ170 (c 1.00,
25
þ
CHCl
3
) {lit.9
[
a]
ꢀ168.09 (c 1.2, CHCl
3
)}. Found: [MþNa]
þ
1
165.0523. C
7
H
10
O
3
Na requires [MþNa] 165.0522; H NMR (CDCl
3
,
5
3
00 MHz) d 1.40 (3H, d, J 6.3 Hz, 6-CH ), 2.31 (1H, dd, J 17.1 and
3
.9 Hz, 5-Heq), 2.42 (1H, ddd, J 17.1, 11.7 and 1.5 Hz, 5-Hax), 3.71 (3H,
References and notes
13
s, OCH
3
), 4.49 (1H, m, 6-H), 5.10 (1H, d, J 1.5 Hz, 3-H); C NMR
, 125 MHz) 20.4, 34.5, 55.9, 72.1, 90.1, 167.3, 172.7;
982, 1692, 1620, 1393, 1240, 1205, 1053, 1005, 990, 851 cm ; m/z
1. Vollmer, W. Appl. Microbiol. Biotechnol. 2006, 73, 37–47.
(
2
CDCl
3
d
n
max
ꢀ
1
2. Wang, J.; Galgoci, A.; Kodali, S.; Herath, K. B.; Jayasuriya, H.; Dorso, K.; Vicente,
F.; Gonzalez, A.; Cully, D.; Bramhill, D.; Singh, S. J. Biol. Chem. 2003, 278, 44424–
44428.
þ
þ
1
13
(
ESI ) 142.9 [MþH] . The H and C NMR data were in agreement
9
3
4
. Weisleder, D.; Lillehoj, E. B. Tetrahedron Lett. 1971, 12, 4705–4706.
. Suzuki, K.; Nozawa, K.; Nakajima, S.; Kawai, K. Chem. Pharm. Bull. 1990, 38,
with the literature.
3
180–3181.
5. Ayer, W. A.; Craw, P. A.; Nozawa, K. Can. J. Chem. 1991, 69, 189–191.
. Arnone, A.; Assante, G.; Montorsi, M.; Nasini, G. Phytochemistry 1995, 38, 595–
97.
. (a) Evans, G. E.; Leeper, F. J.; Murphy, J. A.; Staunton, J. J. Chem. Soc., Chem.
3
.11. (R)-3,4-Dihydro-10-hydroxy-7-methoxy-9-methoxy-
6
ethoxymethoxy-3-methyl-1H-naphtho[2,3-c]pyran-1-one 18
5
7
To a solution of diisopropylamine (0.39 mL, 2.74 mmol) in THF
Commun. 1979, 205–206; (b) Carpenter, T. A.; Evans, G. E.; Leeper, F. J.; Staunton,
J.; Wilkinson, M. R. J. Chem. Soc., Perkin Trans. 1 1984, 1043–1051.
ꢁ
(
1
12 mL) at ꢀ60 C was added n-butyllithium (1.6 M in hexane,
8. Deshpande, V. H.; Khan, R. A.; Rai, B.; Ayyangar, N. R. Synth. Commun. 1993, 23,
.7 mL, 2.74 mmol). The reaction mixture was allowed to warm to
2337–2345.
ꢁ
ꢁ
ꢀ
10 C and stirred for 15 min. After cooling to ꢀ70 C, ortho-toluate
9
. Drochner, D.; M u¨ ller, M. Eur. J. Org. Chem. 2001, 211–215.
1
7 (320 mg, 1.12 mmol) in THF (1 mL) was added and stirring was
10. Donner, C. D.; Gill, M.; Tewierik, L. M. Molecules 2004, 9, 498–512.
11. Donner, C. D. Tetrahedron Lett. 2007, 48, 8888–8890.
ꢁ
continued for 10 min at ꢀ70 C. To the resultant red solution was
1
2. Volkmann, R. A.; Kelbaugh, P. R.; Nason, D. M.; Jasys, V. J. J. Org. Chem. 1992, 57,
352–4361.
13. Mori, K.; Ikunaka, M. Tetrahedron 1984, 40, 3471–3479.
added the (R)-lactone 16 (160 mg, 1.12 mmol) in THF (1 mL) and the
4
ꢁ
mixture was allowed to warm to 0 C over 30 min. The reaction was

4012
N.P.H. Tan, C.D. Donner / Tetrahedron 65 (2009) 4007–4012
1
1
4. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–394.
5. (a) Carlson, R. M.; Oyler, A. R. Tetrahedron Lett. 1974, 15, 2615–2618; (b) Carlson,
R. M.; Oyler, A. R.; Peterson, J. R. J. Org. Chem. 1975, 40, 1610–1616.
6. The addition of alcohols to -acetylenic esters is known to lead pre-
dominantly to the Z-isomer: Winterfeldt, E. Angew. Chem., Int. Ed. Engl. 1967, 6,
23–434.
17. Tan, N. P. H.; Donner, C. D. Tetrahedron Lett. 2008, 49, 4160–4162.
18. Zeeck, A.; Ru
, P.; Laatsch, H.; Loeffler, W.; Wehrle, H.; Z a¨ hner, H.; Holst, H.
b
Chem. Ber. 1979, 112, 957–978.
1
a
,
b
19. Although 2 and 3 possess different descriptors, (S) and (R), respectively, they
are stereochemically analogous and would therefore be expected to exhibit
similar Cotton effects in their circular dichroism spectra.
4