Naphthopyranone synthesis via the tandem Michael-Dieckmann reaction of ortho-toluates with 5,6-dihydropyran-2-ones

Article abstract of DOI:10.1016/j.tetlet.2008.04.112

The tandem Michael-Dieckmann reaction between a series of ortho-toluates and the α,β-unsaturated lactone 25 is described. The tandem reaction delivers substituted naphthopyranones in moderate (20-49%) yields, whilst limitations in the tolerance of this reaction for different substituents on the ortho-toluate are identified. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2008.04.112

Tetrahedron Letters 49 (2008) 4160–4162
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Tetrahedron Letters
journal homepage: http://www.elsevier.com/locate/tetlet
Naphthopyranone synthesis via the tandem Michael–Dieckmann reaction
of ortho-toluates with 5,6-dihydropyran-2-ones
*
Nichole P. H. Tan, Christopher D. Donner
School of Chemistry, The University of Melbourne, Victoria 3010, Australia
Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The tandem Michael–Dieckmann reaction between a series of ortho-toluates and the a,b-unsaturated
lactone 25 is described. The tandem reaction delivers substituted naphthopyranones in moderate
(20–49%) yields, whilst limitations in the tolerance of this reaction for different substituents on the
ortho-toluate are identified.
Received 20 March 2008
Accepted 21 April 2008
Available online 24 April 2008
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
R1
R1 OH
O
The tandem Michael–Dieckmann reaction of ortho-toluates
with cyclic and acyclic b-alkoxy-a,b-unsaturated ketones, the
Staunton–Weinreb annulation, has been used regularly as an effec-
tive method for preparing polycyclic frameworks in the synthesis
of natural products and related structures. Less commonly
exploited is the tandem Michael–Dieckmann reaction of ortho-tol-
uates 1 with a,b-unsaturated d-lactones 2 (Scheme 1), a strategy
first reported by Staunton and co-workers,1 which provides a con-
cise method for the rapid construction of naphthopyranones 3.
Since the first reported application of this methodology to the
synthesis of toralactone,1 this approach has been exploited in the
synthesis of a select group of naphthopyranone-based natural
products including vioxanthin,2 semivioxanthin3,4 and cassiaside
C2.5 Furthermore, naphthopyranones prepared using this method-
ology have served as useful synthetic intermediates in the prepara-
tion of other structure classes including naphthalenes,6
naphthopyrans7 and pyranonaphthoquinones.8,9 We have applied
the tandem Michael–Dieckmann reaction towards the synthesis
of the extended quinone xylindein10 and, more recently, prepared
the naphthopyranone 3 (R1 = OMe, R2 = CH2CH2OTBS) as an inter-
mediate in the preparation of the pyranonaphthoquinone anti-
biotic kalafungin 4 (Scheme 1).9
Although the minimum requirement of having an oxygen sub-
stituent at C-2 of the ortho-toluate (e.g., 1 R1 = OMe) is recog-
nized1,11 and 2,4-dioxygenated ortho-toluates have found regular
use,1–8 the tolerance of this reaction for further oxygen substitu-
ents has not been reported. Having successfully applied this gen-
eral methodology to the synthesis of kalafungin 4, we sought to
explore the potential scope of this strategy for the preparation of
pyranonaphthoquinones related to kalafungin 4, such as arizonin
B1 5.
O
CO2Me
LDA
2
O
O
+
4
R2
MeO
OH
R2
Me
3
2
1
O
O
OH
O
O
MeO
O
O
O
O
O
O
arizonin B1 5
kalafungin 4
Scheme 1. Synthesis of naphthopyranones 3 via the tandem Michael–Dieckmann
reaction.
The focus of our study was to prepare a series of naphthopyra-
nones 3 (R2 = CH2CH2OTBS, Scheme 1) that incorporate additional
oxygen substituents in the peripheral aromatic ring. Thus, we
firstly needed to prepare a series of oxygenated ortho-toluates
(Table 1, 14–24). Methyl 2-methylbenzoate 16 was prepared from
ortho-toluic acid, whilst the 2-methoxytoluate 17 was prepared
from 2,3-dimethylanisole12 and the 2,4-dimethoxytoluate 21 from
methyl acetoacetate.13 Methyl opianate 12 (Scheme 2) serves as a
suitable precursor for preparation of the 2,3-dimethoxytoluate 14,
and is available from opianic acid.14 However, we chose to prepare
14 from the more readily available 3,4-dimethoxybenzaldehyde 6.
Thus, conversion of the aldehyde 6 to the cyclic acetal 8 proceeded
smoothly using 1,3-propanediol/trimethyl orthoformate/TBATB.15
Directed ortho-metalation of 8 followed by trapping with methyl
chloroformate gave the benzoate 10 that could not be completely
freed from unreacted 8. Exposure of the mixture of 8 and 10 to acid
delivered the benzaldehyde 12 in 57% yield over three steps
from 6. Finally, reduction of the aldehyde 12 gave the required
* Corresponding author. Tel.: +61 3 8344 2411; fax: +61 3 9347 8189.
E-mail address: cdonner@unimelb.edu.au (C. D. Donner).
0040-4039/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.112

N. P. H. Tan, C. D. Donner / Tetrahedron Letters 49 (2008) 4160–4162
4161
Table 1
Products and yields from reactions of ortho-toluates 14–24 with lactone 25
MeO
MeO
MeO
R1
CO2Me
R1
R1
a
Product (yield)a
b
Entry
ortho-Toluate
O
O
O
CHO
R2
CO2Me
R2
R2
O
1
—
6 R1=OMe, R2=H
7 R1=H, R2=OMe
10 R1=OMe, R2=H
11 R1=H, R2=OMe
8 R1=OMe, R2=H
9 R1=H, R2=OMe
Me
16
MeO
MeO
MeO
MeO
OH
O
R1
CO2Me
Me
R1
CO2Me
CHO
2
3
CO2Me
c
d
O
2
3
5
Me
OTBS
R2
R2
17
26 (46%)
MeO OH
12 R1=OMe, R2=H
13 R1=H, R2=OMe
14 R1=OMe, R2=H
15 R1=H, R2=OMe
O
MeO
MeO
CO2Me
MeO
O
Scheme 2. Reagents and conditions: (a) 1,3-propanediol, (MeO)3CH, Bu4NÁBr3, 16 h
(92% for 8, 97% for 9); (b) nBuLi, ClCO2Me, Et2O, À78 °C to rt, 16 h; (c) 10% HCl, THF,
16 h (62% for 12, 79% for 13, two steps); (d) H2, 50 psi, 5% Pd/C, MeOH, 6 h (95% for
14, 53% for 15).
Me
OTBS
27 (~5%)b
OH
14
R1O
R1O
O
R2O
CO2Me
Me
R2O
O
OH
O
O
CO2Me
OTBS
O
O
+
X
X
18 R1 = Me, R2 = Piv
19 R1, R2 = –CH2–
28 R1 = Me, R2 = Piv (0%)c
29 R1, R2 = –CH2– (0%)c
30 R1 = MEM, R2 = Me (0%)c
Me
4
5
6
OTBS
MeO
OTBS
14-24
25
26-35
20 R1 = MEM, R2 = Me
Scheme 3. Tandem Michael–Dieckmann reaction of ortho-toluates 14–24 with
lactone 25. Reagents and conditions: LDA (2 equiv), THF, À65 °C to rt (30 min).
RO
RO
OH
O
CO2Me
O
MeO
Me
MeO
OTBS
30 min gave the naphthopyranone 26 in 46% yield. At higher
temperature (À40 °C), incomplete consumption of lactone 25 was
observed, whilst at lower temperature (À78 °C) for longer periods
the lactone 25 also underwent elimination to form the correspond-
ing conjugated dienoic acid.
7
8
9
21 R = Me
22 R = MEM
23 R = TBS
31 R = Me (41%)
32 R = MEM (49%)
33 R = TBS (0%)d
MeO
MeO
OH O
The optimized conditions were then applied to the series of
ortho-toluates collected in Table 1. As expected, unsubstituted tol-
uate 16 failed to give any naphthopyranone. This is consistent with
previous reports that have shown that an oxygen substituent ortho
to the carboxymethyl group is required for successful reaction.1,11
Somewhat unexpectedly the 2,3-dimethoxytoluate 14 (entry 3)
gave only trace amounts of the naphthopyranone 27.
Believing that the electron-donating nature of the additional
methoxy group was disfavouring deprotonation of the para-
disposed methyl group in 14, the pivaloyl protected derivative 18
(entry 4) was prepared. However, this toluate also failed to under-
go the tandem reaction. Similarly unsuccessful were the reactions
of the methylenedioxy derivative 19 and the MEM protected
toluate 20. Subsequently, successful reaction between the 2,5-
dimethoxytoluate 15 (entry 10) and lactone 25 indicated that elec-
tronic factors are not the only consideration in this process. The
2,4-dimethoxytoluate 21 (entry 7) reacted efficiently (41%), whilst
the MEM ether analogue 22 gave a further slight improvement in
yield (49%). However, the bulkier TBS protecting group in 23 was
not compatible with this process. The only identifiable product
from the combination of the TBS-protected toluate 23 and lactone
25 appeared to be the product of Michael addition without sub-
sequent cyclization.
CO2Me
Me
O
10
OTBS
MeO
15
MeO
34 (20%)
OH O
MeO
MeO
Br
CO2Me
Me
R
O
11
OTBS
35 (R=Br) + 26 (R=H) (10%)
24
a
Typically, unreacted toluate was also recovered from each reaction. However,
all yields refer to isolated products without adjustment for recovered toluate.
Yield estimated from the 1H NMR spectrum of partially purified product still
b
contaminated with toluate 14.
c
Recovery of toluate, lactone 25 and acid degradation product.
Recovery of 23, 25 and the product of Michael addition.
d
ortho-toluate 14 (95% yield). A similar sequence of reactions was
used to prepare the 2,5-dimethoxytoluate 15 from 2,5-dimethoxy-
benzaldehyde 7. In this case, the benzoate 13 was obtained in 77%
yield over three steps from 7. Reduction of the aldehyde 13 gave
the required ortho-toluate 15 in somewhat lower yield (53%), due
to concomitant formation of 4,7-dimethoxyphthalide (27% yield),
resulting from lactonization of the intermediate benzyl alcohol.
With this initial series of ortho-toluates in hand, we began to
explore their propensity to undergo a tandem Michael–Dieckmann
reaction with lactone 25 (Scheme 3). The lactone 25 is itself avail-
able in 48% yield over six steps from aspartic acid.9 Treatment of
2-methoxytoluate 17 with LDA (2 equiv) at À65 °C followed by
addition of lactone 25 and warming to room temperature over
The exploration of ortho-toluates 14 and 18–20 (entries 3–6)
possessing oxygens at both C-2 and C-3 was driven by our interest
in gaining direct access to a naphthopyranone framework that
incorporates the necessary functionality for eventual elaboration
to arizonin B1 5. With the failure of these substrates, we turned
to the brominated toluate 24 (entry 11). The toluate 24 reacted
with lactone 25 to deliver a mixture of products identified as the
desired 8-bromonaphthopyranone 35 and the de-halogenated

4162
N. P. H. Tan, C. D. Donner / Tetrahedron Letters 49 (2008) 4160–4162
material 26. Unfortunately, the poor yield for this reaction pre-
cludes this as a viable method for accessing arizonin B1 5.
Some tentative conclusions may be drawn from the above re-
sults. Previously, it has been proposed that the oxygen substituent
ortho to the carbonyl hinders nucleophilic attack at the carbonyl
through both steric and electronic effects, and that after deproto-
nation, the toluate anion forms an extended enolate structure.1,11
Such an anion may be stabilized by the ortho oxygen substituent
through chelation. However, the necessary orientation for chela-
tion of the lithium cation between the enolate oxygen and the
lone-pair of electrons on the C-2 oxygen may not be achieved
effectively when the C-2 oxygen possesses either (i) a bulky pro-
tecting group (entry 9), (ii) a conformationally restrictive protec-
tive group (entry 5) or (iii) if a second neighbouring group at C-3
(entries 3, 4 and 6) is present to exert a further steric influence.
Electronic factors presumably have some role; however, the rela-
tive success of the 2,5-dimethoxytoluate 15 (entry 10) in compar-
ison to the 2,3-dimethoxytoluate 14 (entry 3) shows that this is not
the only consideration in the tandem Michael–Dieckmann process.
In conclusion, the tandem Michael–Dieckmann reaction be-
tween a series of ortho-toluates and the b-methoxy-a,b-unsatu-
rated lactone 25 has been explored and limitations identified.
Application of this methodology to the synthesis of biologically sig-
nificant naphthopyranone natural products is under way; however,
further work will be necessary to develop an efficient method for
incorporation of additional oxygen substituents for the proposed
synthesis of arizonin B1 5.
Acknowledgements
Financial support from the Australian Research Council through
the Centres of Excellence program is gratefully acknowledged. Pro-
fessor Carl Schiesser, The University of Melbourne, is acknowl-
edged for useful discussions.
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