Total synthesis of (-)-xanthatin

Article abstract of DOI:10.1016/j.tetlet.2008.03.081

The first enantioselective total synthesis of xanthatin, a xanthanolide sesquiterpenoid exhibiting potent antibacterial activity against MRSA, has been accomplished from an optically pure bicyclic lactone, previously synthesized by our group.

Full text of DOI:10.1016/j.tetlet.2008.03.081

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3504–3506
Total synthesis of (À)-xanthatin
Hiromasa Yokoe, Masahiro Yoshida, Kozo Shishido *
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
Received 23 February 2008; revised 17 March 2008; accepted 18 March 2008
Available online 20 March 2008
Abstract
The first enantioselective total synthesis of xanthatin, a xanthanolide sesquiterpenoid exhibiting potent antibacterial activity against
MRSA, has been accomplished from an optically pure bicyclic lactone, previously synthesized by our group.
Ó 2008 Elsevier Ltd. All rights reserved.
Xanthanolides1 are a class of sesquiterpenoids found in
a plant of the Xanthium family. Because of their intriguing
biological profiles, several members of this class have
attracted considerable attention among synthetic organic
chemists. Xanthatin (1) was first isolated from Xanthium
pennsylvanicum by Little et al.2 in their examination of
the cocklebur for its antibacterial principle. Its structure
was firmly established by Geissman et al.3 who suggested
that 1 would be derived from xanthinin during isolation,
particularly on column chromatography.4 Xanthatin (1)
has also been isolated from X. strumarium,1 X. sibiricum,5
and X. macrocarpum,6 and exhibits potent antibacterial
activity against Staphylococcus aureus species, including
MRSA.5 The unique structural features of the xanthano-
lides have provided the motivation for the development
of synthetic strategies toward these natural products.7 In
this Letter, we report the first total synthesis of (À)-xanth-
atin (1) (Fig. 1).
We recently reported the total synthesis of sundiversifo-
lide (2),8 in which the bicyclic lactone 6 played an impor-
tant role, and suggested that 6 could also be utilized as a
common chiral building block in the total synthesis of 1.
The retrosynthetic analysis is shown in Scheme 1. Xantha-
tin (1) could be obtained by a cross metathesis7a,b between
methyl vinyl ketone and 3, which would be prepared from 4
by a methylenation at C11 (xanthatin numbering) and
dehydration sequence. The ethanol side chain in 4 could
be installed using the carbonyl ene reaction9 of 5, which
in turn would be constructed from 6 via a key inversion
at C8 and the introduction of the exo-methylene group
at C1.
The treatment of 6,8 which has been prepared diastereo-
selectively from 4-pentenal via a 9-step sequence in 50%
overall yield, with diethylamine and aluminum chloride10
HO
H
H
O
1
O
O
11
O
O
H
H
1
HO
3
4
H
H
8
O
O
11
O
O
H
H
2
TBSO
1
H
ref. 8
H
1
8
2
O
O
Fig. 1. Structures of (À)-xanthatin (1) and (+)-sundiversifolide (2).
O
OMe
H
H
6
5
*
Corresponding author. Tel./fax: +81 88 6337294.
Scheme 1. Retrosynthetic analysis of 1.
E-mail address: shishido@ph.tokushima-u.ac.jp (K. Shishido).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.081

H. Yokoe et al. / Tetrahedron Letters 49 (2008) 3504–3506
3505
1) TBDPSCl, imidazole
4-DMAP, CH2Cl2
rt, quant.
Ph
p-nitrobenzoic acid
DIAD, Ph3P
TBSO
H
Et2NH, AlCl3
THF, rt, 84%
HO
8
6
O AlMe
2
OH
CONEt2
2) AcOH, acetone
H2O, rt
toluene, rt, 92%
Ph
H
11 (MAPH)
H
5
O
7
trioxane, toluene
3) TPAP, NMO
NOE
–78 °C, 66%
4A MS, CH2Cl2
rt, 88% (2 steps)
OMe
H
11
LiOH•H2O
O
H
TBSO
H
H
then 1N HCl
1
8
HO
1) o-nitrophenyl
selenocyanate
nBu3P, THF, rt
O
O
TBDPSO
MeOH, rt
90%
TBAF, THF
rt, 81%
NO2
O
H
H
H
8
9
CONEt2
4
O
2) H2O2 (aq.)
THF, 40 °C
90% (2 steps)
O
1) TPAP, NMO
4A MS, CH2Cl2
0 ˚C, 92%
H
O
12
1) DIBAH, toluene
–78 ˚C
HO
H
O
5
LiTMP then MeI
H
H
O
2) TMSCH2MgCl
Et2O, 0 ˚C,
2) p-TsOH•H2O
MeOH, reflux
78% (2 steps)
THF, –78 ~ –40 ˚C
OMe
H
3) KH, THF, reflux
quant. (2 steps)
10
84%
O
H
O
H
14
13
Scheme 2. Synthesis of 5. DIAD = diisopropyl azodicarboxylate;
DIBAH = diisobutylaluminum hydride; TPAP = tetrapropylammonium
perruthenate; NMO = N-methylmorpholine N-oxide.
H2O2 (aq.)
CH2Cl2
0 °C
LDA then (PhSe)2
HMPA, THF
H
O
11
–78 ~ –40 °C
7
3
O
SePh
98%
89%
H
15
provided the amide alcohol 7. The Mitsunobu reaction
with DIAD, triphenylphosphine, and p-nitrobenzoic acid11
cleanly produced the inverted benzoate 8, which was then
subjected to alkaline hydrolysis followed by acidic treat-
ment to afford the trans-fused bicyclic lactone 9 in good
overall yield. The desired stereochemistry at C8 was
secured by the observation of a diagnostic NOE between
C8-H and C1-H. After protection of the lactone carbonyl
in 9 as the acetal, the secondary alcohol in 10 was oxidized
with TPAP and NMO to provide the corresponding
ketone. Attempted introduction of the exo-methylene moi-
ety at C1 using conventional methods (e.g., Wittig and
Horner–Wadsworth–Emmons protocols, and the Nozaki–
Lombardo method12) gave only unsatisfactory results.
However, Peterson olefination conditions13 provided an
excellent result. Thus, sequential treatment of the ketone
with TMSCH2MgCl and KH in refluxing THF produced
5 quantitatively (Scheme 2).
NOE
NMes
Ru
MesN
Cl
O
Cl
H
O
O
16
O
H
methyl vinyl ketone
CH2Cl2, reflux, 49%
(–)-Xanthatin (1)
Scheme 3. Completion of total synthesis of 1. LiTMP = lithium
tetramethylpiperidide.
selenide 15 as a single diastereomer. The assignment of the
stereochemistry at C11 was made based on the NOE
between C7-H and C11-Me. Selenide 15 was then exposed
to hydrogen peroxide to furnish the requisite triene 3 selec-
tively. Final construction of the butenone side chain at C1
was successfully accomplished by a chemoselective cross
metathesis18 employing the Hoveyda catalyst 1619,7b to
provide (À)-xanthatin (1),20 whose spectral data (1H and
13C NMRs) were identical with those of natural xanthatin
(Scheme 3).
In summary, we have completed the first enantioselec-
tive total synthesis of the antibacterial xanthanolide, xanth-
atin (1), starting from the optically pure cis-fused bicyclic
lactone 6 employing an efficient conversion to the trans-
fused lactone 9 as the key step. The synthetic route devel-
oped here holds considerable promise for the synthesis of
related natural products.
Installation of the olefinic ethanol appendage at C1 was
realized by the treatment of 5 with methylaluminum
bis(2,6-diphenylphenoxide) (MAPH)9 and trioxane to give
11. Sequential protection of the primary hydroxyl group as
the TBDPS ether, regeneration of the lactone moiety, and
desilylation provided 4 in good overall yield. Exposure of
n
4 to o-nitrophenyl selenocyanate and Bu3P gave the sele-
nide, which was oxidized with hydrogen peroxide14,15 to
give diene 13. Attempted introduction of the exo-methyl-
ene group at C11 under conditions employing the
Eschenmoser salt16 led to the formation of 3 in quite low
yield. Therefore, compound 13 was treated with LiTMP
and methyl iodide to give, as a single product, 14, which
was identical with the compound prepared by Morken,
et al., during their total synthesis of (À)-11a,13-dihydrox-
anthatin.7a Introduction of a phenylselenyl group at C11
was carried out with LDA and diphenyl diselenide17 to give
Acknowledgments
We thank Dr. Youichi Sato of the University of Toku-
shima for providing us with the spectral data of natural
xanthatin and valuable information. This work was

3506
H. Yokoe et al. / Tetrahedron Letters 49 (2008) 3504–3506
Lett. 2005, 7, 4621; Kummer, D. A.; Brenneman, J. B.; Martin, S. F.
Tetrahedron 2006, 62, 11437.
8. Yokoe, H.; Sasaki, H.; Yoshimura, T.; Shindo, M.; Shishido, K. Org.
Lett. 2007, 9, 969.
9. Maruoka, K.; Concepcion, A. B.; Murase, N.; Oishi, M.; Hirayama,
N.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 3943.
10. Hanryu, N.; Aoki, T.; Mino, T.; Sakamoto, M.; Fujita, T. Tetra-
hedron: Asymmetry 2000, 11, 4127.
supported in part by a Grant-in-Aid for the Scientific
Research on Priority Areas (No.18032052 for K.S.) from
the Ministry of Education, Culture, Sports, Science and
Technology (MEXT).
References and notes
11. Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
12. Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1978,
19, 2417; Lombardo, L. Org. Synth. 1986, 65, 81.
1. McMillan, C.; Chavez, P. I.; Plettman, S. G.; Marby, T. J. Biochem.
Syst. Ecol. 1975, 2, 181.
13. Vazquez, A.; Williams, R. M. J. Org. Chem. 2000, 65, 7865.
14. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485.
15. Sato, K.; Yoshimura, T.; Shindo, M.; Shishido, K. J. Org. Chem.
2001, 66, 309; Kamei, T.; Shindo, M.; Shishido, K. Tetrahedron Lett.
2003, 44, 8505.
2. Little, J. E.; Foote, M. W.; Johnstone, D. B. Arch. Biochem. 1950, 27,
247.
3. (a) Geissman, T. A.; Deuel, P.; Bonde, E. K.; Addicott, F. A. J. Am.
Chem. Soc. 1954, 76, 685; (b) Deuel, P.; Geissman, T. A. J. Am. Chem.
Soc. 1957, 79, 3778.
4. It was demonstrated by Geissman that xanthinin could be converted
to xanthatin by passing it through a column of alumina using ether as
eluent.3a
16. Clair, J. J. L.; Lansbury, P. T.; Zhi, B.-X.; Hoogsteen, K. J. Org.
Chem. 1995, 60, 4822.
17. Grieco, P. A.; Miyashita, M. J. Org. Chem. 1974, 39, 120.
18. Attempted cross-metathesis using Grubbs’ Type I and II7a catalysts
proceeded but with poor conversion (23% and 32% yield respectively).
19. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
20. Mp 114.5–115.2 °C (EtOH); lit.2 mp 114.5–115 °C (EtOH); lit.3b mp
112–114 °C (EtOH). [a]D À17.8 (CHCl3, c 0.14); lit.2 [a]D À20.0
(EtOH); lit.3a [a]D À20.0 (CHCl3, c 2.44).
5. Sato, Y.; Oketani, H.; Yamada, T.; Shingyouchi, K.; Ohtsubo, T.;
Kihara, M.; Shibata, H.; Higuti, T. J. Pharm. Pharmacol. 1997, 49,
1042.
6. Pinel, B.; Audo, G.; Mallet, S.; Lavault, M.; Poype, F. D. L.;
Seraphin, D.; Richomme, P. J. Chromatogr. A 2007, 1151, 14.
7. Total synthesis of (À)-11a,13-dihydroxanthatin; (a) Evans, M. A.;
Morken, J. P. Org. Lett. 2005, 7, 3371. Total synthesis of (+)-8-epi-
xanthatin; (b) Kummer, D. A.; Brenneman, J. B.; Martin, S. F. Org.