Total synthesis of (±)-epimagnolin A

Article abstract of DOI:10.1016/S0040-4039(00)01958-4

The first total synthesis of (±)-epigmagnolin A was was achieved employing a C-H insertion reaction reaction to generate selectively the bicyclic framework with the exo, endo-stereochemistry.

Full text of DOI:10.1016/S0040-4039(00)01958-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 473–475
Total synthesis of (±)-epimagnolin A
Richard C. D. Brown,* Carole J. R. Bataille and Jeremy D. Hinks
Department of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
Received 10 October 2000; accepted 2 November 2000
Abstract—The first total synthesis of (±)-epimagnolin A was achieved employing a C–H insertion reaction to generate selectively
the bicyclic framework with the exo,endo-stereochemistry. © 2001 Elsevier Science Ltd. All rights reserved.
The crude Chinese drug from the flower buds of Magno-
lia fargesii known as shin-i has been a source of many
natural products including biologically active lignans.
ible with electron-rich aryl groups, but should also allow
different oxygenated aryl groups to be installed at the 2-
and 6-positions. To assess the utility of our CꢀH inser-
tion approach in this regard we investigated the synthe-
sis of epimagnolin A (1).
1
–5
Recent bioassay-guided fractionation studies on shin-i
yielded a new lignan epimagnolin A with growth in-
hibitory activity against the larvae of Drosophila
2
melanogaster. Structure 1 was assigned to the new
The synthesis commenced with a [2+2] cycloaddition
reaction between amide 4 and allyl ether 11 (Scheme
lignan on the basis of mass spectroscopic evidence
1
13
10
combined with H and C NMR data (Fig. 1).
1), employing modified reaction conditions reported to
9
allow the use of acid-sensitive substrates. In the case of
The widespread occurrence of furofuran lignans com-
bined with a variety of interesting biological activities
has stimulated significant interest in their synthesis.
trimethoxy-substituted arylacetamides 4, even with the
precaution of adding anhydrous K CO to the reaction
2
3
6
–8
mixture, the yield of the desired cyclobutanone 5 was
disappointing. A modest improvement was obtained by
careful temperature control, holding the reaction mix-
ture at 0°C for 2 h. Separation of the trans-isomer 5
We recently reported an approach to exo,endo-furofura-
nones similar to 1 involving a highly diastereoselective
CꢀH insertion reaction, and used the method to synthe-
sise asarinin (2) (Fig. 1), which bears the same aryl
†
from the minor cis-isomer was achieved by column
9
substituents at the 2- and 6-positions. A generally
chromatography prior to Baeyer–Villiger oxidation,
useful synthetic approach to lignans should be compat-
which afforded the lactone 6 in 66% yield.
Figure 1.
*
Corresponding author. Fax: (0)23 80596805; e-mail: rcb1@soton.ac.uk
We were unable to determine the ratio of isomers present in the crude reaction mixture by 1H NMR. Only a trace of what was presumed to
†
be the cis-isomer was present after flash chromatography.
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01958-4

4
74
R. C. D. Brown et al. / Tetrahedron Letters 42 (2001) 473–475
Scheme 1. Reagents and conditions: (a) i. Tf O, CH Cl , −25°C; ii. K CO , 2,6-di-tert-butylpyridine, 11, −25 to 0°C; iii. NaHCO
3
2
2
2
2
3
(
aq), rt; (b) H O , AcOH; (c) i. LiHMDS, THF, −78°C; ii. F CCH OCOCF , −78°C; (d) p-nitrobenzenesulfonylazide, Et N,
2 2 3 2 3 3
CH CN; (e) Rh (OAc) , THF; (f) LiAlH , THF.
3
2
4
4
Scheme 2. Reagents and conditions: (a) MsCl, pyridine, CH Cl , rt.
2
2
A decarbonylative approach was employed to achieve
the conversion of lactone 6 to the diazo-lactone 8,
which displayed spectroscopic data consistent with
those reported for epimagnolin A.
11
2
forming the trifluoroacylated lactone 7 prior to diazo-
transfer. Diazo-lactone 8 was sufficiently stable to sur-
vive purification by flash chromatography on silica,
although complete removal of the sulfonamide by-
product, arising from the diazo-transfer reagent, was
not possible. Fortunately, the presence of 4-nitro-
phenylsulfonamide did not appear to affect the subse-
quent CꢀH insertion reaction, which proceeded readily
upon the addition of catalytic rhodium(II) acetate
dimer. The formation of the exo,endo-furofuranone 9
was confirmed by means of GOESY experiments.
In summary, a short and diastereoselective synthesis of
(±)-epimagnolin A has been described employing a
highly diastereoselective CꢀH insertion reaction of an
a-diazo-g-butyrolactone. We are currently investigating
improved routes to a-diazo-g-lactones and lactams and
investigating the scope of their CꢀH insertion reactions
in the synthesis of various bicyclic and tricyclic
scaffolds.
Conversion of 9 to (±)-epimagnolin A was achieved
following the method employed during the synthesis of
asarinin. However, the sensitivity of the methoxy sub-
stituted compounds was apparent during the reduction
Acknowledgements
We extend our gratitude to The Royal Society
(R.C.D.B.), The University of Southampton (J.D.H.)
and AstraZeneca (unrestricted grant) for supporting
this research. We also wish to acknowledge the use of
the EPSRC’s Chemical Database Service at Dares-
of lactone 9 using LiAlH , which afforded the desired
4
2° alcohol 10 and small quantities of by-products possi-
bly arising from over reduction. Mesylation of 10 re-
sulted in closure of the second tetrahydrofuran ring,
affording the racemic natural product (Scheme 2),
12
bury.

R. C. D. Brown et al. / Tetrahedron Letters 42 (2001) 473–475
475
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