Total synthesis of 10-norparvulenone and of O-methylasparvenone using a xanthate-mediated free radical addition - Cyclization sequence

Article abstract of DOI:10.1021/ol035394o

(Matrix presented) A short synthesis of (±)-10-norparvulenone and (±)-O-methylasparvenone was developed starting from commercially available m-methoxyphenol, hinging on a xanthate-mediated addition - cyclization sequence for the construction of the α-tetr

Full text of DOI:10.1021/ol035394o

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3717-3719
Total Synthesis of 10-Norparvulenone
and of O-Methylasparvenone Using a
Xanthate-Mediated Free Radical
Addition−Cyclization Sequence
Alejandro Cordero Vargas, Be´atrice Quiclet-Sire, and Samir Z. Zard*
Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique,
91128 Palaiseau, France
zard@poly.polytechnique.fr
Received July 25, 2003
ABSTRACT
A short synthesis of (±)-10-norparvulenone and (±)-O-methylasparvenone was developed starting from commercially available m-methoxyphenol,
hinging on a xanthate-mediated addition
−cyclization sequence for the construction of the
r-tetralone subunit.
The R-tetralone derivatives 10-norparvulenone (1)1 and
O-methylasparvenone (2)2 are two natural products recently
discovered, whose structures are characterized by a bicyclic
carbon framework possessing a carbonyl function, one meth-
oxy group, and two or three hydroxyl groups. (Figure 1).
10-Norparvulenone 1 is a novel anti-influenza virus anti-
biotic recently isolated from Microsphaeropsis sp., and pre-
liminary in vitro assays have shown this compound to be a
very promising anti-influenza virus drug.1 To the best of our
knowledge, there is as yet no total synthesis for this structure.
O-Methylasparvenone (2) exhibits very different pharma-
cological activities. It acts as a nitrogen-free serotonin
antagonist and could be used in the treatment of depression
and obsessive-compulsive disorders.3 The synthesis of this
natural product and some other analogues was reported by
Bo¨s et al.3,4 In an interesting sequence, they were able to
prepare compound 2 in seven steps from 3,4,5-trimethoxy-
benzaldehyde as starting material. Although this synthesis
Figure 1.
is an effective way to prepare compound 2 and some
analogues, it lacks flexibility and cannot, for example, be
easily transposed to a synthesis of norparvulenone. In
particular, the construction of the 4-hydroxy-1-tetralone motif
was not straightforward. A few years ago, we reported a new
method for the preparation of R-tetralones using xanthate
free radical chemistry.5 This method allows the synthesis of
a wide variety of substituted tetralones under mild and neutral
conditions. Herein, we report the first total synthesis of 1
and a new total synthesis of 2 using a xanthate-mediated
free radical addition-cyclization sequence as the key step.
(1) Fukami, A.; Nakamura, T.; Kim, Y-P.; Shiomi, K.; Hyashi, M.; Nagai,
T.; Yamada. H; Komiyama, K.; Omura, S. J. Antibiot. 2000, 53, 1215.
(2) (a) Simpson, T. J.; Stenzel, D. J. J. Chem. Soc., Chem. Commun.
1981, 139. (b) Shan, R.; Stadler, M.; Anke, H.; Sterner, O. J. Nat. Prod.
1997, 60, 804.
(3) Bo¨s, M.; Canesso, R.; Inoue-Ohga, N.; Nakano, A.; Takehana, Y.;
Sleight, A. J. Bioorg. Med. Chem. 1997, 5, 2165.
(4) Bo¨s, M.; Stadler, H.; Wichmann, J.; Jenck, F.; Martin, J. R.; Moreau,
J-L.; Sleight, A. J. HelV. Chim. Acta 1998, 81, 525.
10.1021/ol035394o CCC: $25.00
© 2003 American Chemical Society
Published on Web 08/30/2003

Since no total synthesis has been reported for 1, we first
focused our attention on this compound. The general features
of our route are outlined in Scheme 1. 10-Norparvulenone
also a xanthate that can be used as a starting point for another
radical sequence, in this case to construct the six-membered
ketonic ring of R-tetralone 4.
Our synthesis starts with the preparation of bromoaceto-
phenone 7 in 60% yield by a Friedel-Crafts acylation of
commercially available m-methoxyphenol using the condi-
tions reported by Sawada et al.7 (Scheme 3). Treatment of
Scheme 1. Retrosynthetic Plan for Synthesis of 1
Scheme 3. Preparation of Tetralone 9
(1) would be prepared from aldehyde 3 by simple reduction
of the aldehyde and deprotection of the benzylic hydroxy
group. To avoid selectivity problems in the formylation
reaction, we planned to introduce the aldehyde function at a
late stage in the synthesis.
A Vilsmeier-Haack formylation would allow us to obtain
the desired aldehyde from 4, which in the key step of the
synthesis would be obtained in a convergent manner from
an acetophenone xanthate (5) and the appropriate protected
vinyl alcohol (6), the latter serving as an effective radical
trap. The radical sequence for the synthesis of the key
R-tetralone (4) is outlined in Scheme 2. We had shown that
xanthates such as 5 could undergo a radical chain reaction
to olefinic trap 6 to give adduct 6a where a new carbon-
carbon bond and carbon-sulfur bond have been formed.6
This process has the great advantage that compound 6a is
the latter with potassium ethyl xanthate in acetone at 0 °C
afforded the desired radical precursor 8 in quantitative yield.
The next step for the preparation of the key bicyclic
intermediate 4 started with acetylation of the hydroxyl group
followed by radical addition of the xanthate onto vinyl
pivalate using dilauroyl peroxide (DLP) as initiator in 1,2-
dichloroethane (DCE) as solvent, yielding a 1:1 mixture of
the deprotected xanthate 9a and the desired adduct 9b. The
former was converted into the latter under the same acety-
lation conditions. The overall yield of 9b was 75% from 8.
When a refluxing solution of 9b in DCE was treated with
1.2 equiv of DLP (added portionwise), tetralone 10 was
obtained in 48% yield.
Scheme 2. Mechanism for the Radical Sequence
As can be seen in Scheme 3, partial deprotection of the
phenolic group forced us to introduce an extra step in the
reaction sequence. This problem was solved by simply
adding acetic anhydride to the medium in the radical reaction,
thus further demonstrating the tolerance and flexibility of
xanthate chemistry.6 This modification thus was incorporated
(5) Liard, A.; Quiclet-Sire, B.; Saicic, R. N.; Zard, S. Z. Tetrahedron
Lett. 1997, 38, 1759.
(6) (a) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1977, 36, 672. (b) Zard,
S. Z. In Radicals in Organic Synthesis; Renaud, P., Sibi, M., Eds.; Wiley
VCH: Weinheim, 2001; p 90.
(7) Swada, S.; Miyasaka, T.; Arakawa, K. Chem. Pharm. Bull. 1977,
25, 3370.
3718
Org. Lett., Vol. 5, No. 20, 2003

in a one-pot conversion of xanthate 8a into aldehyde pre-
cursor 4. We therefore subjected 8a to the three-step one-
pot reaction sequence shown in Scheme 4 and obtained
Scheme 6. Synthesis of (()-10-Norparvlenone 1 and
(()-O-Methylasparvenone 2
Scheme 4. One-Pot Preparation of Tetralone 11
tetralone 11 in an overall yield of 36 % from 8 without
optimization of the reaction conditions (Scheme 4).
The next step in our synthesis was the introduction of the
formyl group in order to get the desired precursor of 10-nor-
parvulenone (1). The application of one of the most common
formylation reaction procedures, the Vilsmeier-Haack reac-
tion8 (POCl3/DMF) to tetralone 11, as well as some variations
(PCl5/DMF and (COCl)2/DMF), were unsuccessful. We then
attempted direct hydroxyalkylation of the phenol moiety.
Application of the method reported by Nagata et al.9 using
paraformaldehyde and phenylboronic acid in refluxing
toluene in the presence of trifluoroacetic acid (TFA) did not
give the expected benzodioxaboronate but unsaturated ketone
12 instead (Scheme 5), probably via an aldol/dehydration
and 2 became straightforward. Thus, selective reduction of
the aldehyde with NaBH3CN in methanol, followed by
saponification of the trimethylacetyl ester group, furnished
10-norparvulenone 1 in 68% yield. The spectroscopic and
analytical data of 1 were identical to those of the natural
product.1
Because of the close relationship between 1 and 2, we
decided to use aldehyde 13 as the common intermediate for
the synthesis of both natural products. Access to compound
2 was accomplished by converting the aldehyde into olefin
14 using typical Wittig conditions, without protection of the
phenolic hydroxyl group. The yield was only moderate
(39%), but having such a styrenyl group provides yet another
handle for further manipulations. Hydrogenation over pal-
ladium on charcoal and saponification of the pivaloate group
finally completed the sequence. In this way, (()-O-methyl-
asparvenone was isolated in 84% yield; its spectroscopic and
analytical properties of 2 were identical to those reported in
the literature.3
Scheme 5. Unexpected Formation of Compound 12
In conclusion, the first total synthesis of (()-10-norpar-
vulenone (1) has been accomplished in only five separate
steps starting from commercially available m-methoxyphenol,
with the final product isolated in 14% unoptimized overall
yield. The total synthesis of (()-O-methylasparvenone (2)
required six steps from the same starting material with an
overall yield of 7%. The strategy we have implemented is
convergent, efficient, and highly flexible, allowing a great
variety of modifications at several positions around the
molecules.
reaction.10 Even if this compound was not expected, it could
be useful as a Michael acceptor for the synthesis of numerous
analogues.
The introduction of the formyl substituent was finally
achieved using the method described by Gross et al.11
(Scheme 6). When a cold (-10 °C) solution of tetralone 11
in dichloromethane was treated with TiCl4 and dichloro-
methyl methyl ether, aldehyde 13 was obtained in 96% yield.
With precursor 13 in hand, completion of the synthesis of 1
Acknowledgment. We thank CONACyT for its generous
financial support to A.C.V.
(8) For a review, see: Jutz, A. AdV. Org. Chem. 1976, 9, 225.
(9) Nagata, W.; Okada, K.; Aoki, T. Synthesis 1979, 365.
(10) For reviews on the Prins reaction, see: (a) Adams, D. R.; Bhatnagar,
S. P. Synthesis 1977, 661. (b) Arundale, E.; Mikeska, L. A. Chem. ReV.
1952, 51, 505.
(11) (a) Gross, H.; Rieche, A.; Mattey, G. Chem. Ber. 1963, 96, 308.
(b) Cresp, T. M.; Sargent, M. V.; Elix, J. A.; Murphy, D. P. H. J. Chem.
Soc., Perkin Trans. 1 1973, 340.
Supporting Information Available: Detailed description
of experimental procedures and spectral information and
analyses for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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