A metalation strategy for the construction of functionalized naphthalenes: The first synthesis of guieranone A

Article abstract of DOI:10.1016/j.tetlet.2005.08.127

The first synthesis of the natural product guieranone A is described, demonstrating a one-pot procedure for the synthesis of protected-1,3,6,8- tetraoxygenated naphthalenes and a subsequent directed metalation synthesis of 2-keto naphthalenes.

Full text of DOI:10.1016/j.tetlet.2005.08.127

Tetrahedron
Letters
Tetrahedron Letters 46(2005) 7 61 9–7 62 1
A metalation strategy for the construction of functionalized
naphthalenes: the first synthesis of guieranone A
Malcolm W. B. McCulloch and Russell A. Barrow*
Department of Chemistry, The Australian National University, Canberra ACT 0200, Australia
Received 4 July 2005; revised 16August 2005; accepted 23 August 2005
Available online 16September 2005
Abstract—The first synthesis of the natural product guieranone A is described, demonstrating a one-pot procedure for the synthesis
of protected-1,3,6,8-tetraoxygenated naphthalenes and a subsequent directed metalation synthesis of 2-keto naphthalenes.
Ó 2005 Elsevier Ltd. All rights reserved.
Syntheses of 2-acyl substituted naphthalenes are difficult
to achieve regioselectively, yet these compounds are key
building blocks for a large number of naphthalene-based
natural products including naphthopyrones and some
naphthoquinones. This diverse class of natural products
possesses a range of biological activities and new meth-
of protected naphthalenes such as 7 and 8 from the
phenylacetic acid derivative 5.
Our synthesis (Scheme 1) began with methyl 3,5-di-
methoxyphenylacetate (4), which was readily prepared
6
following PangÕs method. This was acylated with acetic
1
ods to synthesize them are required. This communica-
anhydride containing a catalytic amount of perchloric
tion outlines
a
short and efficient synthesis of
acid, in a slight modification of BycroftÕs procedure to
give 5.
2
7
guieranone A (1) showcasing a directed metalation
strategy that we are developing which should provide
access to a variety of naphthalene-based natural prod-
ucts and derivatives.
Treatment of 5 in DMF with 3.3 equiv of sodium hyd-
ride gave the naphthalene disodium salt intermediate
6
, via a Dieckmann-type cyclization. The excess of base
8
Guieranone A (1) is an antifungal agent isolated from the
leaves of the plant Guiera senegalensis by Silva and
prevented formation of the phenol 2, which contains a
peri six-centered hydrogen bond. These peri hydrogen
bonds make phenol substitution difficult; for example,
Kamila et al. found that the phenol in naphthalene 3
2
Gomes. The position of the butenone moiety in guiera-
none A—situated on the naphthalene ring ortho to two
methoxy groups—suggested an ortho-directed metala-
tion reaction as an appropriate synthetic strategy. We
proposed to utilize both the synthetically useful methoxy
directed metalation group (DMG) and the powerful
9
was relatively unreactive towards substitution.
Attempts to synthesize protected 1,3,6,8-tetraoxygen-
ated naphthalenes by quenching the intermediate 6 with
soft electrophiles such as iodomethane or MOM-Cl,
repeatedly led to the formation of complex mixtures.
However, when the relatively hard electrophiles di-
methyl sulfate or diethylcarbamoyl chloride were uti-
lized, the naphthalenes 7 and 8 were formed cleanly in
85% and 89% respective yields. Soft electrophiles can
3
diethyl carbamate DMG in the synthesis of the natural
product, and in preparing 2-keto naphthalene analogues.
While the naphthalene synthon required to prepare 1 via
this strategy is known, previous syntheses of 1,3,6,8-
4
,5
tetramethoxynaphthalene (7) have been inefficient.
We have developed a high-yielding, one-pot synthesis
Me
H
Me
H
OMe OMe O
O
O
O
O
8
1
8
1
Keywords: Guieranone; Naphthalenes; Metalation; Natural product;
Dieckmann cyclization.
MeO
OMe
MeO
OH MeO
*
Corresponding author. Tel.: +61 2 61253419; fax: +61 2 61250760;
e-mail: rab@anu.edu.au
1
2
3
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.127

7620
M.W.B.McCulloch, R.A.Barrow / Tetrahedron Letters 46 (2005) 7619–7621
OMe
OMe O
OMe O
(
i)
(ii)
1
+
2 Na
MeO
MeO
MeO
O
4
MeO
4
O
MeO
5
O
6
(
iii)
OMe OR
O
1
OMe OR
1
8
a' 1'
(iv)
4
2
MeO
OR
R=Me
R=CONEt2
MeO
OR
4'
1
9
7 R=Me
8 R=CONEt2
Scheme 1. Reagents, conditions and yields: (i) Ac
2
O, HClO
, 72 h, rt, then reflux 2 h, 89%; (iv) for 1, 1.4 equiv n-BuLi, 1.4 equiv TMEDA, THF, ꢁ78 °C, 1 h, then 70 min, rt, then ꢁ78 °C,
.6equiv crotonic anhydride to rt, 28% (unoptimized); for 9, 1.3 equiv t-BuLi, 1.3 equiv TMEDA, THF, ꢁ78 °C, 45 min, then 40 min, ꢁ40 °C, then
78 °C, 2.0 equiv crotonic anhydride to rt, 61% (unoptimized).
4 3 2 4
(cat), 24 h, 85%; (ii) 3.3 equiv NaH, DMF, 2 h; (iii) for 7, (CH ) SO , 12–48 h, 85%; for
8, ClCONEt
2
1
ꢁ
1
3
presumably react with the soft carbon center in 6, given
that 6 is effectively an enolate.
Table 1. Comparison of synthetic and natural guieranone (1)
NMR shifts
C
a
2,b
Position
Synth. d
C
Lit.
With naphthalenes 7 and 8 in hand, a final metalation
step gave us our desired 2-keto naphthalenes. Thus,
when 7 was treated with 1.4 molar equivalents of n-BuLi
and TMEDA, followed by excess crotonic anhydride,
guieranone A (1) was obtained in an unoptimized 28%
isolated yield (ꢀ80% based on recovered starting mate-
rial). Similarly, when 8 was treated with 1.3 molar equiva-
lents of t-BuLi and TMEDA, followed by excess
crotonic anhydride, 9 was obtained in 61% isolated
1
2
3
4
197.8
135.2
149.4
18.5
155.6155.6
64.2
122.7
156.4
56.3
103.4
140.7
99.8
160.8
56.1
98.4
158.6158.7
55.8
111.5
197.9
135.2
149.3
18.4
0
0
0
0
0
0
1
1 -OMe
2
3
64.2
122.8
156.5
56.3
103.4
140.8
99.8
160.9
56.1
98.3
3
4
4
5
6
6
7
8
-OMe
1
0
yield. While these results are unoptimized, the higher
0
a
yield of 9 reflects the relative strength of the carbamate
0
0
0
0
0
0
3
DMG.
-OMe
The spectroscopic data (IR, MS, and NMR) of our syn-
thetic guieranone A sample supported the assigned
structure 1; the data were identical to those reported
8 -OMe
8a0
55.8
111.6
2
13
for the natural product. Table 1 shows that the
C
a
NMR shifts for synthetic 1 match those of the natural
product within the bounds of spectral resolution.
75 MHz APT; CD OD.
100 MHz; CD OD.
3
3
b
Silva reported that guieranone A showed potent activity
against the fungus C.cucumerinum .2 To explore the
extent of this antimicrobial activity we have tested 1
against a range of microorganisms using the disk diffu-
sion method at concentrations up to 0.6mg/mL and
found no activity against an unidentified Penicillium
sp. or against any of the following bacterial pathogens:
S.aureus , E.coli , P.aeruginosa , S.epidermidis , or M.
smegmatis. These results indicate that guieranone A pos-
sesses selective and specific antifungal activity.
electrophiles in the cyclization/protection and metala-
tion steps, this methodology can give a range of highly
functionalized naphthalene derivatives. This will be fur-
ther elaborated in a forthcoming full paper.
1
1
Acknowledgements
One of us (M.W.B.M) would like to thank the ANU for
an ANU PhD Graduate School Scholarship.
In conclusion, we have completed the first synthesis of
guieranone A (1) and developed a versatile synthesis of
2
-keto naphthalenes. By starting with various phenyl-
Supplementary data
acetic acid derivatives, and using a range of different
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.08.127.
Freshly prepared by DCC dehydration of crotonic acid and then
distilled.

M.W.B.McCulloch, R.A.Barrow / Tetrahedron Letters 46 (2005) 7619–7621
7621
References and notes
CH
3
)
2
)]. EIMS m/z (%): 418 (53), 100 (100), 72 (55);
requires
HREI-MS m/z: found 418.2096(C 22
30 2 6
H N O
ꢁ1 1
4
18.2104). Compound 9: IR (film): 1720, 1630 cm ; H
1
2
3
4
. McCulloch, M. W. B.; Barrow, R. A. Molecules, in press.
. Silva, O.; Gomes, E. T. J.Nat.Prod. 2003, 66, 447–449.
. Snieckus, V. Chem.Rev. 1990, 90, 879–933.
3
NMR (300 MHz, CDCl ) d: 7.53 (1H, s), 7.13 (1H, dq,
1
6
3
5.6, 6.9 Hz), 6.66 (1H, d, 2.0 Hz), 6.39 (1H, d, 2.0 Hz),
.03 (1H, dq, 15.6, 1.8 Hz), 3.81 (3H, s), 3.72 (3H, s), 3.42–
.15 (8H, m), 1.92 (3H, dd, 6.9, 1.8 Hz), 1.18–0.97 (12H,
. Eisaku, M.; Shibata, S. Chem.Pharm.Bull.
765–1771.
. Sargent, M. V. J.Chem.Soc ,. Perkin Trans.1
35.
. Pang, Y. P.; Kozikowski, A. P. J.Org.Chem. 1991, 56,
499–4508.
. Bycroft, B. W.; Roberts, J. C. J.Chem.Soc. 1962, 2063–
064.
. Bycroft, B. W.; Roberts, J. C. J.Chem.Soc. 1963, 4868–
872.
1967, 15,
1
1
3
m); C APT-NMR (75 MHz, CDCl
3
) d: 164.1 (C-1),
5
6
7
8
9
1987, 231–
0
0
1
63.9 (CONEt
2
), 158.8 (C-6 ), 156.6 (C-8 ), 152.9
2
0
(CONEt ), 146.2 (C-3), 145.5, 143.5, 136.9 (C4a ), 121.8
2
0
0
0
0
(
C-2), 120.7 (C-2 ), 116.7 (C-4 ), 112.6(C-8a ), 99.1 (C-7 ),
4
0
0
0
9
4
1
4
8.7 (C-5 ), 55.8 (6 -OCH
1.9, 38.1 (CON(CH CH
2.6(CON(CH CH ) )]; EIMS m/z (%): 486(28), 418 (34),
03 (20), 346(27), 100 (100), 72 (54); HREI-MS m/z:
requires 486.2366). Com-
pound 1: H NMR (300 MHz, CD OD) d: 7.01 (1H, s),
.81 (1H, d, 2.0 Hz), 6.61 (1H, dq, 15.5, 6.7 Hz), 6.47 (1H,
3
3
), 55.2 (8 -OCH ), [42.7, 42.1,
2
2
3 2
) )], 18.0 (C-4), [14.0, 13.4, 13.2,
2
3 2
4
. Kamila, S.; Mukherjee, C.; Mondal, S. S.; De, A.
Tetrahedron 2003, 59, 1339–1348.
0. Satisfactory spectroscopic data were obtained for all
34 2 7
found 486.2366 (C26H N O
1
3
6
1
1
d, 2.0 Hz), 6.35 (1H, dq, 15.5,1.6 Hz), 3.91 (3H, s), 3.88 (3H,
s), 3.83 (3H, s), 3.71 (3H, s), 1.90 (3H, dq, 6.7, 1.6 Hz); H
NMR (300 MHz, CDCl ) d: 6.83 (1H, s), 6.66 (1H, d,
compounds. Selected data: Compound 7: H NMR
1
(
2
(
8
300 MHz, CDCl ) d: 6.62 (2H, d, 2.3 Hz), 6.36 (2H, d,
3
1
3
.3 Hz), 3.92 (6H, s), 3.88 (6H, s); C APT-NMR
) d: 158.6, 158.4, 139.0 (C-4a), 108.5 (C-
a), 98.3 (C-4), 96.5 (C-2), 56.0 (C-1–OCH ), 55.1 (C-3–
3
2
.0 Hz), 6.58 (1H, dq, 15.5, 6.5 Hz), 6.40 (1H, d, 2.0 Hz),
75 MHz, CDCl
3
6
.38 (1H, dq, 15.5, 1.5 Hz), 3.93 (3H, s), 3.88 (3H, s), 3.82
3
1
3
(
3H, s), 3.76(3H, s), 1.86(3H, dd, 6. 5, 1.5 Hz);
C APT-
OCH ); EIMS m/z (%): 248 (100), 205 (9), 175 (12); HREI-
3
1
3
NMR (75 MHz, CD OD) see Table 1; C APT-NMR
MS m/z: found 248.1049 (C14
H
16
O
4
requires 248.1049).
3
ꢁ
1
1
0
0
(
8
1
75 MHz, CDCl ) d: 195.5 (C-1 ), 159.0 (C-6 ), 157.4 (C-
3
Compound 8: IR (film): 1720 cm ; H NMR (300 MHz,
CDCl ) d: 7.32 (1H, d, 2.3 Hz), 6.83 (1H, d, 2.3 Hz), 6.67
1H, d, 2.2 Hz), 6.41 (1H, d, 2.2 Hz), 3.84 (3H, s), 3.82
3H, s), 3.55–3.33 (8H, m, CON(CH CH ), 1.31–1.19
); C APT-NMR (75 MHz,
) d: 158.4 (C-6), 156.6 (C-8), 154.6 (CONEt ), 153.7
CONEt ), 149.4 (C-3), 148.1 (C-1), 137.5 (C-4a), 115.2
0
0 0 0
), 155.2 (C-3 ), 154.5 (C-1 ), 147.0 (C-3), 138.8 (C-4a ),
3
0
0
0
34.2 (C-2), 122.0 (C-2 ), 110.6(C-8a ), 101.9 (C-4 ), 98.3
(
(
(
0 0 0 0
C-5 ), 97.0 (C-7 ), 63.9 (C-1 -OCH ), 55.8 (C-8 -OCH ),
3 3
(
2
3
)
2
1
3
0
0
5
5.5 (C-3 -OCH
3
), 55.2 (C-6 -OCH
3
), 18.3 (C-4); HREI-
requires 316.1311).
2 3 2
12H, m, CON(CH CH )
MS m/z: found 316.1310 (C18
H
20
O
5
CDCl
(
(
5
(
3
2
1
1. National Committee for Clinical Laboratory Standards
NCCLS). Performance Standards for Antimicrobial Disk
2
(
C-4), 113.5 (C-8a), 113.2 (C-2), 98.5 (C-5), 98.3 (C-7),
5.4 (OCH ), 55.2 (OCH ), [42.4, 42.1, 42.0, 41.6
CON(CH CH ) )], [14.1, 13.9, 13.4, 13.1 (CON(CH -
Susceptibility Tests; Approved standard. 7th edn., M2-A7.
NCCLS, Wayne, PA, 2000.
3
3
2
3 2
2