Studies on the resorcylates: biomimetic total syntheses of (+)-montagnetol and (+)-erythrin

Article abstract of DOI:10.1016/j.tetlet.2009.11.134

6-(2,4-Dioxopentyl)-2,2-trimethyl-4H-1,3-dioxin-4-one on reflux in toluene gave MeCOCH₂COCH₂COCH{double bond, long}C{double bond, long}O, which cyclized to 6-(2-oxopropyl)-4-hydroxy-2H-pyran-2-one or was trapped with alcohols to produce resorcylate esters. The method was used for the synthesis of both enantiomers of montagnetol and erythrin.

Full text of DOI:10.1016/j.tetlet.2009.11.134

Tetrahedron Letters 51 (2010) 783–785
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies on the resorcylates: biomimetic total syntheses of (+)-montagnetol
and (+)-erythrin
Jean-François Basset a, Colin Leslie b, Dieter Hamprecht b, Andrew J. P. White a, Anthony G. M. Barrett a,
*
a Department of Chemistry, Imperial College, London SW7 2AZ, England, United Kingdom
b GlaxoSmithKline Centro Ricerche, Via Fleming 4, I-37135 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
6-(2,4-Dioxopentyl)-2,2-trimethyl-4H-1,3-dioxin-4-one on reflux in toluene gave MeCOCH2COCH2
COCH@C@O, which cyclized to 6-(2-oxopropyl)-4-hydroxy-2H-pyran-2-one or was trapped with alcohols
to produce resorcylate esters. The method was used for the synthesis of both enantiomers of montagnetol
and erythrin.
Received 11 October 2009
Revised 22 November 2009
Accepted 30 November 2009
Available online 3 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The orsellinic acid unit 1 occurs widely in natural products,
including montagnetol (2) and the anti-oxidant1 erythrin (3), both
isolated from the lichen Roccella montagnei (Fig. 1).2 The structures
of montagnetol (2) and erythrin (3) were confirmed by synthesis,3
although the absolute stereochemistry has not yet been assigned.
Herein, we report a convergent, novel synthesis of diketo-1,3-
dioxinone 10, its varied cyclization reactions, and its application
to the synthesis of both enantiomers of (+)-montagnetol (2) and
(+)-erythrin (3) thereby determining the absolute configuration
of these natural products.
The thermolytic ketene generation, trapping, and aromatization
were applied to the total synthesis of (+)-montagnetol (2) and
(+)-erythrin (3), respectively.
Thermolysis of dioxinone 10 in the presence of benzyl-pro-
tected erithritols 15a10 and 15b gave the triketo-esters 16a and
16b, respectively.11 NMR analysis in CDCl3 showed these com-
pounds to exist as mixtures of keto and enol tautomers.12 Aldol
cyclization and aromatization followed by hydrogenolysis of the
benzyl groups gave 18 and (+)-montagnetol (2), respectively
(Scheme 4).
Recently, we reported efficient biomimetic syntheses of bioac-
tive resorcylate natural products 4 via thermolysis, ketene trap-
ping, and aromatization, starting from dioxinones 5 (Scheme 1).4
In the process of optimizing the aromatization step in the syn-
thesis of these natural products, a model system, diketo-1,3-dioxi-
none 10 was examined. It was found that 10 can undergo different
cyclization reactions depending on the reaction conditions.
Dioxinone 10 was synthesized by thermolysis of commercially
available dioxinone 6, which underwent a retro-Diels–Alder5 reac-
tion at 90 °C to form acyl-ketene 7, which was trapped with benzo-
triazole 8 to form amide 9 in quantitative yield.6 Subsequent
crossed Claisen condensation7 via reaction of the lithium enolate
from dioxinone 6 with amide 9 gave diketo-1,3-dioxinone 10 as
a 5:95 mixture of keto–enol tautomers in 53% yield over two steps
(Scheme 2).8
Reaction between dioxinone 10 and phenol 17a at 110 °C failed
to give the corresponding aryl triketo-ester, indicating that the
OH
O
OH
OH
O
OH
O
OH
OH
HO
O
HO
orsellinic acid (1)
(+)-montagnetol (2)
OH
OH
OH
OH
O
O
OH
O
(+)-erythrin (3)
HO
Figure 1. Natural products containing the orsellinic acid unit.
Dioxinone 10 undergoes cyclization using triethylamine,
1,4-diazabicyclo(2.2.2)octane, or N,N-4-dimethylaminopyridine to
give the benzo[1,3]dioxinone 11 (Scheme 3). Alternatively, ther-
molysis in toluene containing methanol and aromatization with
cesium carbonate followed by acidification gave the resorcylate
13 (87%). Finally, thermolysis of dioxinone 10 alone in toluene
solution gave the pyrone 14 (68%).
OH
O
1) retro Diels-Alder,
R1OH
O
O
O
O
OR1
R2
O
2) aromatization
HO
R2
5
4
* Corresponding author.
E-mail address: agm.barrett@imperial.ac.uk (A.G.M. Barrett).
Scheme 1. Retrosynthetic approach to build 6-alkyl-2,4-dihydroxybenzoic acid
unit 4.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.134

784
J.-F. Basset et al. / Tetrahedron Letters 51 (2010) 783–785
O
O
O
PhMe,
90 °C
O
C
OH
O
OBn
17a, (2S,3R)
H
O
N
17b, (2R,3S)
OBn O
O
7
N
6
OBn OBn
TFAA,
PhMe
N
O
+
8
BnO
OBn O
20a, (2S,3R)
20b, (2R,3S)
OH
O
O
O
O
O
O
O
N
BnO
HO
N
1) LiN(SiMe3)2, 6
N
19
2) 9
53% two steps
10
OH
O
O
OH
9
OH
O
Scheme 2. Synthesis of diketo-1,3-dioxinone 10.
H2, Pd/C,
EtOAc
OH
OH
O
21, (2S,3R), 63% two steps
3, (2R,3S), 61% two steps15
O
O
Et3N, CH2Cl2
96%
10
O
Scheme 5. Synthesis of (ꢀ)-erythrin (21) and (+)-erythrin (3). (see above-
HO
mentioned reference for further information.)
11
OH
O
O
O
O
OMe
The two enantiomers of montagnetol, 18 and 2, were examined
for their optical rotations, compared with the natural product,
showing 2 (2R,3S) to have the true configuration. Both enantiomers
(ꢀ)-erythrin (21) and (+)-erythrin (3) were compared with an
authentic sample of erythrin, and chiral HPLC analysis was fully
consistent with the natural product configuration being (2R,3S)-
erythrin (3).
MeOH,
PhMe
1) Cs2CO3, MeOH
2) Acid work-up
87%
OMe
10
10
10
O
HO
12
13
MeOH, MS 4Å, CH2Cl2
13
sealed tube, 100 °C, 82%
OH
O
Acknowledgments
O
PhMe,
68%
We thank GlaxoSmithKline for the generous endowment (to
A.G.M.B.), GlaxoSmithKline Verona for grant support (to J.F.B.), P.
R. Haycock and R. N. Sheppard, both at Imperial College London,
for high-resolution NMR spectroscopy and Professor V. Kar-
unaratne (University of Peradeniya, Sri Lanka) for generously pro-
viding a sample of the natural product (+)-erythrin.
O
14
Scheme 3. Different cyclization reactions of diketo-1,3-dioxinone 10.
O
O
OBn
OBn
3
OBn
Supplementary data
10, PhMe,
O
2
OBn
HO
110 ºC
OBn
O
OBn
15a, (2S,3R)
15b, (2R,3S)
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.134.
16a, (2S,3R)
16b, (2R,3S)
References and notes
1) Cs2CO3, MeOH
2) Acid work-up
1. Choudhary, M. I.; Ali, S.; Thadani, V. M.; Karunaratne, V. U.S. Patent application
publication 0,048,332 A1, 2009.
2. Rao, S. V.; Seshadri, T. R. Proc. Ind. Acad. Sci. Sect. A 1941, 13A, 199.
3. Manaktala, S. K.; Neelakantan, S.; Seshadri, T. R. Tetrahedron 1966, 22, 2373.
4. Navarro, I.; Basset, J.-F.; Hebbe, S.; Major, S. M.; Werner, T.; Howsham, C.;
Bräckow, J.; Barrett, A. G. M. J. Am. Chem. Soc. 2008, 130, 10293.
5. Hyatt, J. A.; Feldman, P. L.; Clemens, R. J. J. Org. Chem. 1984, 49, 5105.
6. This activated amide intermediate exists as a 1:1 mixture of keto and enol
forms. As benzotriazole 9 is prone to decomposition, it was used directly in the
next step. The NMR analysis of intermediate 9 was measured in THF-d8.
7. Katritzky, A. R.; Wang, Z.; Wang, M.; Hall, C. D.; Suzuki, K. J. Org. Chem. 2005, 70,
4854.
OH
O
OH
OH
O
OBn
OH
OBn
O
O
H2, Pd/C,
EtOAc
OH
OBn
HO
HO
17a, (2S,3R), 77%
17b, (2R,3S), 78%
18, (2S,3R), 81%
2, (2R,3S), 81%9
Scheme 4. Synthesis of (ꢀ)-montagnetol (18) and (+)-montagnetol (2). (see above-
8. It was observed that the yield decreased if benzotriazole was not removed
before column chromatography, due to aromatization to 11. To avoid this side
product, the mixture was washed with a pH 9 buffer solution to remove
benzotriazole and suppress the rate of the aromatization reaction.
mentioned reference for further information.)
9. The optical rotations of compounds 18, (2S,3R) and 2, (2R,3S) were ½a D20
ꢀ10.1
ꢁ
(acetone, c 0.5) and ½a D20
ꢁ
=+11 (acetone, c 0.4), respectively; these data were
phenol in 17a was of insufficient nucleophilicity. Consequently, a
more classical approach was applied starting from the protected
orsellinic acid 1913 which underwent an esterification reaction
with phenol 17a or 17b using activation with trifluoroacetic
anhydride14 to provide the diesters 20a and 20b, respectively. Deb-
enzylation by hydrogenolysis afforded 21 and 3, respectively
(Scheme 5).
compared with those of the isolated natural (+)-montagnetol2
(acetone).
½ ꢁ +12.6
a 2D0
10. Soriente, A.; De Rosa, M.; Trincone, A.; Sodano, G. Bioorg. Med. Chem. Lett. 1995,
5, 2321.
11. Compounds 16a and 16b are stable at room temperature, but are very sensitive
to base or acid.
12. Deuterium exchange occurs in methanol-d4 leading to the disappearance of the
keto–enol proton in the proton NMR spectrum.

J.-F. Basset et al. / Tetrahedron Letters 51 (2010) 783–785
785
13. Vicart, N.; Ortholand, J.-Y.; Emeric, G. Y.; Greiner, A. Tetrahedron Lett. 1994, 35,
15. The optical rotations of compounds 21, (2S,3R) and 3, (2R,3S) were ½a D20
ꢁ
ꢀ8.2
3917.
(MeOH,
c
0.2) and ½a 2D0
ꢁ
+9 (MeOH, c 0.2), respectively; these data were
14. This is a modified procedure of: Wang, P.; Zhang, Z.; Yu, B. J. Org. Chem. 2005,
70, 8884.
compared with those of the isolated natural (+)-erythrin, kindly provided by
Professor V. Karunaratne, ½a D20
ꢁ
+7.3 (MeOH, c 0.2).