A short formal total synthesis of (±)-hirsutic acid

Article abstract of DOI:10.1139/v2012-037

A short formal total synthesis of (±)-hirsutic acid is described using a Claisen rearrangement and a radical cascade as the key steps. The radical sequence involves an intermolecular addition of a radical derived from a xanthate followed by a cyclization and transfer of the xanthate group.

Full text of DOI:10.1139/v2012-037

927
A short formal total synthesis of ( )-hirsutic acid
Guillaume Revol, Christian Fuchs, and Samir Z. Zard
Abstract: A short formal total synthesis of ( )-hirsutic acid is described using a Claisen rearrangement and a radical cas-
cade as the key steps. The radical sequence involves an intermolecular addition of a radical derived from a xanthate followed
by a cyclization and transfer of the xanthate group.
Key words: hirsutic acid, complicatic acid, triquinanes, Claisen rearrangement, radical cyclization, xanthates.
Résumé : Une synthèse totale formelle courte de l’acide ( )-hirsutique est décrite, employant comme étapes-clés un réarran-
gement de Claisen et une cascade radicalaire. La séquence radicalaire implique une addition intermoléculaire d’un radical
issu d’un xanthate, suivie d’une cyclisation, puis du transfert du groupe xanthate.
Mots‐clés : acide hirsutique, acide complicatique, triquinanes, réarrangement de Claisen, cyclisation radicalaire, xanthates.
derived from the simple and commercially available ketoester
8.
Introduction
(+)-Hirsutic acid 1 (Fig. 1) was isolated in 1947 from a
fungus (Stereum hirsutum), but its structure was only deter-
mined 20 years later.1,2 It belongs to the family of linear tri-
quinanes and is closely related to (+)-complicatic acid 2, a
secondary metabolite from the fungus Stereum complicatum,
which also produces hirsutic acid.3 The biogenetic precursor
for both compounds is presumably (+)-hirsutene (3), a linear
triquinane isolated from a basidiomycete, Coriolis consors.4
While a few of these natural products exhibit interesting bio-
logical acivities, it is mostly the intricate structure of hirsutic
acid and its congeners that has attracted the attention of syn-
thetic organic chemists over four decades. Thus, no less than
nine total and formal syntheses of hirsutic acid have been re-
ported so far.5–13
Apart from constructing the triquinane skeleton of hirsutic
acid 1, there is the challenge of controlling the stereochemis-
try of seven chiral centers, including the tertiary carboxylic
acid at C-11. This complicates significantly the synthetic
planning in comparison with hirsutene 3 where this carbon
is not chiral and simply bears a geminal dimethyl group. In
contemplating simpler routes to hirsutic acid, we envisaged
the possibility of using the chirality at C-11 to install the re-
maining six chiral centers. Our retrosynthetic analysis is out-
lined in Scheme 1.
Indeed, allylic alcohol 7 had already been prepared by
Kato et al.,14 both as racemate and as optically pure material.
The synthesis of the racemic modification is displayed in
Scheme 2. Treatment of ketoester 8 with methyl iodide and
potassium carbonate accomplished the desired methylation to
give compound 9 in near quantitative yield. The unsaturation
could be introduced using Saegusa’s conditions15 applied on
the corresponding enol silyl ether 10. Unfortunately, enone
11 was obtained in a variable overall yield ranging from
12% to 51%. Nevertheless, this was sufficient to confirm the
selectivity of the reduction step leading to allylic alcohol 7.
Using Luche conditions,16 the reduction at –40 °C fur-
nished an 80:20 mixture of allylic alcohol 7 and completely
reduced alcohol 12, respectively, in 65% combined yield.
Both the yield and the selectivity could be increased by low-
ering the reaction temperature to –78 °C (Scheme 2). Fur-
thermore, we later found that enone 11 could be obtained
more reliably and in much better yield by oxidation of ketone
9 with an excess of 2-iodoxybenzoic acid (IBX), according to
the procedure described by Nicolaou et al.17
The conversion of alcohol 7 into enone intermediate 5 re-
lied on a Claisen rearrangement.18 After a number of mostly
unsuccessful attempts, we finally found that heating a mix-
ture of alcohol 7, n-butyl vinyl ether, and a catalytic amount
of mercuric acetate to 200 °C in a microwave oven for 2 h
furnished the desired aldehyde 14 in 48%–60% yield.19 This
compound was rapidly treated with isopropenylmagnesium
bromide in THF at 0 °C to furnish carbinol 15 in a yield
ranging between 52% and 70%. Oxidation with manganese
dioxide in refluxing dichloroethane (DCE) afforded enone 5,
whereas acetylation gave acetate 16 in 58% and 63% yield,
respectively (Scheme 3).
Intermediate tricyclic enone 4 is a key precursor in several
of the published syntheses. It can be converted into compli-
catic acid in four steps and into hirsutic acid in five steps as
was initially demonstrated by Matsumoto and co-workers6 in
1971. We envisaged obtaining this compound by a radical
addition–cyclization of S-acetyl xanthate 6 on monocyclic
enone 5. This enone could, in principle, be obtained through
a Claisen rearrangement starting from allylic alcohol 7, itself
Received 3 April 2012. Accepted 30 April 2012. Published at www.nrcresearchpress.com/cjc on 15 June 2012.
G. Revol, C. Fuchs, and S.Z. Zard. Laboratoire de Synthèse Organique, CNRS UMR 7652, École Polytechnique, 91128, Palaiseau,
France.
Corresponding author: Samir Z. Zard (e-mail: Samir.Zard@polytechnique.edu).
This article is part of a Special Issue dedictated to Professor Derrick Clive. This paper is dedicated with respect and admiration to Pro-
fessor Derrick Clive.
Can. J. Chem. 90: 927–931 (2012)
doi:10.1139/V2012-037
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Can. J. Chem. Vol. 90, 2012
Fig. 1. (+)-Hirsutic acid and congeners.
Scheme 1. Retrosynthetic analysis for hirsutic acid.
Scheme 2. Synthesis of allylic alcohol 7a.
Scheme 3. Synthesis of enone intermediate 5.
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Revol et al.
929
Scheme 4. Key radical cascade.
We were now in a position to examine the key radical cas-
cade based on xanthate chemistry.20 The anticipated sequence
of intermolecular radical addition – cyclization is outlined in
Scheme 4. In analogy with previous work,21 the acetyl radi-
cal generated from S-acetyl xanthate 6 should add to the
enone in 5, and the resulting adduct radical 17a should
undergo ring closure and transfer of the xanthate group to fi-
nally give bicyclic structure 19 via intermediate radical 18a.
We hoped that the smaller methyl group would occupy the
more congested endo face, resulting in the correct relative
stereochemistry found in hirsutic acid, in preference to the al-
ternative conformation shown as 17b, which would lead to
the epimeric cyclized radical 18b. Reductive removal of the
xanthate group and base-induced Robinson-type annelation
would deliver ultimately tricyclic enone 4, thus completing
the formal synthesis of both complicatic and hirsutic acids.
Unfortunately, our attempts to add S-acetyl xanthate 6 to
enone 5 met with failure. This contrasts with the successful
addition of S-butanoyl xanthate to an enone we achieved a
few years ago.21 We also failed to accomplish an addition of
S-acetyl xanthate 6 to allyl acetate 16. S-Acyl xanthates are
rather labile substances: a small quantity of a nucleophilic
impurity can cause complete decomposition by an ionic chain
process.20a This lability is more pronounced in the smaller
members of the family.
fied our approach by replacing the S-acetyl xanthate 6 with
acetoxy xanthate 20a. This xanthate is readily prepared by
displacement of chloride from 1-acetoxy-1-chloroethane, a
known compound22 obtained by reaction of acetaldehyde
with acetyl chloride in the presence of catalytic zinc chloride
(Scheme 5). However, the addition of xanthate 20a to enone
5 again surprisingly gave a complex mixture from which the
desired bicyclic structure could not be isolated. In contrast,
the reaction with allylic alcohol 15 proceeded as expected to
furnish bicyclic derivative 21, as a complex mixture of dia-
stereoisomers 21a, which were not further purified. Reduc-
tive elimination of the xanthate with triethylammonium
hypophosphite,23 saponification of the acetate group with so-
dium methylate, and oxidation of both alcohol groups with
pyridinium chlorochromate (PCC) gave a 1:4 mixture of two
epimeric diketones (22 and 23) in 42% overall yield from al-
cohol 15. Unfortunately, the major epimer had the wrong rel-
ative stereochemistry. The ratio of the two epimers 22 and 23
could be improved to 1:2 by using xanthate 20b, where the
acetate group was replaced with the bulkier benzoate. The
overall yield of the epimeric mixture of 22 and 23 for the
four steps from allylic alcohol 15 remained roughly the same
(24%–41%).
Both bicyclic diketones are known compounds, and the
correct epimer 22 has indeed been converted into hirsutic
acid by base-induced cyclisation into Matsumoto’s intermediate
Faced with these unexpected setbacks, we slightly modi-
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Can. J. Chem. Vol. 90, 2012
Scheme 5. Final steps in the formal synthesis of ( )-hirsutic acid.
4.6 This completes a short, formal total synthesis of both
( )-complicatic acid and ( )-hirsutic acid. While the key
radical cascade finally succeeded, it is still very far from
perfect. The crude model for the ring closure displayed in
Scheme 4 clearly does not reflect reality. The cyclization
leads to what appears as the slightly more congested and
unwanted isomer. More effort is therefore needed to estab-
lish the best combination of xanthate and allylic alcohol 15
or a derivative thereof that ultimately leads to the greatest
ratio in favour of the desired epimer 22. Some progress
was made using benzoate 20b, and this could perhaps be
improved further. Placing a bulky group on the allylic alco-
hol in 15 could also be used to modify the stereoselectivity.
Indeed, a preliminary small-scale experiment using benzoate
thate chemistry for the construction of polyquinanes through
the combination of the radical process with the powerful
Claisen rearrangement. Finally, this synthesis could be
easily made enantioselective since allylic alcohol 7 has al-
ready been prepared in enantiopure form by Kato et al.14
The methylation of ketoester 8 could also be performed in
an enantioselective manner by the use of a chiral base or
through the use of chiral imines or hydrazones, allowing
the control of the absolute stereochemistry at the very be-
ginning of the synthesis.
Acknowledgement
C.F. and G.R. would like to thank Ecole Polytechnique,
Palaiseau, France, for a scholarship.
24 in combination with xanthate 20b resulted in an approx-
23
imately 2:3 ratio of the desired22 over the undesired,
but
References
this has to be confirmed on a larger scale, and this would
also provide a reliable value for the yield. Nevertheless, de-
spite these various shortcomings, the present route to hirsu-
tic acid is significantly shorter than most of the earlier
syntheses. More generally, it illustrates the potential of xan-
(1) Heatley, N. G.; Jennings, M. A.; Florey, H. W. Br. J. Exp.
Pathol. 1947, 28, 35.
(2) (a) Comer, F. W.; McCapra, F.; Qureshi, I. H.; Trotter, J.;
Scott, A. I. J. Chem. Soc. Chem. Commun. 1965, 310; (b)
Comer, F. W.; McCapra, F.; Qureshi, I. H.; Scott, A. I.
Published by NRC Research Press

Revol et al.
Tetrahedron 1967, 23 (12), 4761. doi:10.1016/S0040-4020(01)
931
(13) Banwell, M. G.; Austin, K. A. B.; Willis, A. C. Tetrahedron
2007, 63 (28), 6388. doi:10.1016/j.tet.2007.03.073.
92573-6; (c) Comer, F. W.; Trotter, J. J. Chem. Soc. Chem.
Commun. 1966, 11; (d) Walker, D. C. J. Chem. Soc. Chem.
Commun. 1967, 1050.
(14) (a) Kato, K.; Suzuki, H.; Tanaka, H.; Miyasaka, T. Tetrahedron
Asymmetry 1998, 9 (6), 911. doi:10.1016/S0957-4166(98)
00065-2; (b) Kato, K.; Suzuki, H.; Tanaka, H.; Miyasaka, T.;
Baba, M.; Yamaguchi, K.; Akita, H. Chem. Pharm. Bull.
(Tokyo) 1999, 47 (9), 1256. doi:10.1248/cpb.47.1256.
(15) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43 (5),
1011. doi:10.1021/jo00399a052.
(16) (a) Luche, J.-L. J. Am. Chem. Soc. 1978, 100 (7), 2226. doi:10.
1021/ja00475a040; (b) Gemal, A. L.; Luche, J.-L. J. Am.
Chem. Soc. 1981, 103 (18), 5454. doi:10.1021/ja00408a029.
(17) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc.
2000, 122 (31), 7596. doi:10.1021/ja001825b.
(3) Mellows, G.; Mantle, P. G.; Feline, T. C.; Williams, D. J.
Phytochemistry 1973, 12 (11), 2717. doi:10.1016/0031-9422
(73)85086-1.
(4) Nozoe, S.; Furukawa, J.; Sankawa, U.; Shibata, S. Tetrahedron
Lett. 1976, 17 (3), 195. doi:10.1016/0040-4039(76)80013-5.
(5) (a) Lansbury, P. T.; Wang, N. Y.; Rhodes, J. E. Tetrahedron
Lett. 1971, 12 (21), 1829. doi:10.1016/S0040-4039(01)87473-
6; (b) Lansbury, P. T.; Wang, N. Y.; Rhodes, J. E. Tetrahedron
Lett. 1972, 13 (20), 2053. doi:10.1016/S0040-4039(01)85038-3.
(6) (a) Sakan, F.; Hashimoto, H.; Ichihara, A.; Shirahama, H.;
Matsumoto, T. Tetrahedron Lett. 1971, 12 (40), 3703. doi:10.
1016/0040-4039(71)80007-2; (b) Hashimoto, H.; Tsuzuki, K.;
Sakan, F.; Shirahama, H.; Matsumoto, T. Tetrahedron Lett.
1974, 15 (43), 3745. doi:10.1016/S0040-4039(01)91998-7; (c)
Hayano, K.; Ohfune, Y.; Shirahama, H.; Matsumoto, T.
Tetrahedron Lett. 1978, 19 (23), 1991. doi:10.1016/S0040-
4039(01)94729-X.
(18) Martín Castro, A. M. Chem. Rev. 2004, 104 (6), 2939. doi:10.
1021/cr020703u.
(19) Huber, R. S.; Jones, G. B. J. Org. Chem. 1992, 57 (21), 5778.
doi:10.1021/jo00047a041.
(20) (a) For reviews on the xanthate radical addition – transfer
process see Zard, S. Z. Angew. Chem. Int. Ed. Engl. 1997, 36
(7), 672. doi:10.1002/anie.199706721; (b) Quiclet-Sire, B.;
Zard, S. Z. Chemistry 2006, 12 (23), 6002. doi:10.1002/chem.
200600510; (c) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem.
2006, 264, 201. doi:10.1007/128_029; (d) Zard, S. Z. Aust. J.
Chem. 2006, 59 (10), 663. doi:10.1071/CH06263; (e) Zard, S.
Z. Org. Biomol. Chem. 2007, 5 (2), 205. doi:10.1039/
b615592h; (f) Quiclet-Sire, B.; Zard, S. Z. Pure Appl. Chem.
2011, 83 (3), 519. doi:10.1351/PAC-CON-10-08-07.
(21) Briggs, M. E.; El Qacemi, M.; Kalaï, C.; Zard, S. Z. Chem.
Commun. (Camb.) 2004, 45, 6017.
(22) (a) Ulich, L. H.; Adams, R. J. Am. Chem. Soc. 1921, 43 (3), 660.
doi:10.1021/ja01436a036; (b) Luk’yanov, S. M.; Borodaev, S.
V.; Borodaeva, S. V. J. Org. Chem. USSR 1983, 19, 1872;
(c) Bagal, S.; Tournier, L.; Zard, S. Z. Synlett 2006, 1485.
doi:10.1002/chin.200643058.
(7) Trost, B. M.; Shuey, C. D.; DiNinno, F., Jr. J. Am. Chem. Soc.
1979, 101 (5), 1284. doi:10.1021/ja00499a043.
(8) (a) Yamazaki, M.; Shibasaki, M.; Ikegami, S. Chem. Lett.
1981, 10 (9), 1245. doi:10.1246/cl.1981.1245; (b) Yamazaki,
M.; Shibasaki, M.; Ikegami, S. J. Org. Chem. 1983, 48 (23),
4402. doi:10.1021/jo00171a054; (c) Shibasaki, M.; Yamazaki,
M.; Iseki, K.; Ikegami, S. Tetrahedron Lett. 1982, 23 (50),
5311. doi:10.1016/S0040-4039(00)85826-8; (d) Nishida, M.;
Iseki, K.; Shibasaki, M.; Ikegami, S. Chem. Pharm. Bull.
(Tokyo) 1990, 38 (12), 3230. doi:10.1248/cpb.38.3230.
(9) (a) Greene, A. E.; Luche, M.-J.; Deprès, J.-P. J. Am. Chem.
Soc. 1983, 105 (8), 2435. doi:10.1021/ja00346a054; (b)
Greene, A. E.; Luche, M.-J.; Serra, A. A. J. Org. Chem.
1985, 50 (21), 3957. doi:10.1021/jo00221a001.
(10) Magnus, P.; Exon, C.; Albaugh-Robertson, P. Tetrahedron
1985, 41 (24), 5861. doi:10.1016/S0040-4020(01)91425-5.
(11) Schuda, P. F.; Phillips, J. L.; Morgan, T. M. J. Org. Chem.
1986, 51 (14), 2742. doi:10.1021/jo00364a023.
(23) (a) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C.
Tetrahedron Lett. 1992, 33 (39), 5709. doi:10.1016/0040-
4039(92)89012-2; (b) Boivin, J.; Jrad, R.; Juge, S.; Nguyen, V.
T. Org. Lett. 2003, 5 (10), 1645. doi:10.1021/ol0342610.
(12) Singh, V.; Tosh, D. K.; Mobin, S. M. Tetrahedron Lett. 2004,
45 (8), 1729. doi:10.1016/j.tetlet.2003.12.095.
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