Enantioselective syntheses of (+)-xylarenal A and ent-xylarenal A

Article abstract of DOI:10.1021/jo0502450

(Chemical Equation Presented) The total synthesis of the sesquiterpenoid xylarenal A is reported. This first synthetic entry to an eremophilane terpenoid with an exocyclic vinyl aldehyde unit involves the use of the bicyclic enone (+)-3, which after a γ-o

Full text of DOI:10.1021/jo0502450

Enantioselective Syntheses of
(+)-Xylarenal A and ent-Xylarenal A
Sandra D´ıaz, Asensio Gonza´lez, Ben Bradshaw,
Javier Cuesta, and Josep Bonjoch*
Laboratori de Quı´mica Orga`nica, Facultat de Farma`cia,
Universitat de Barcelona, Av. Joan XXIII s/n, 08028
Barcelona, Spain
josep.bonjoch@ub.edu
Received February 7, 2005
FIGURE 1. Structure of xylarenals and related sesquiterpe-
noids.
Xylarenal A (1) was isolated from the fermentation
broth of a fungal strain, Xylaria persicaria, by a team of
Merck scientists,4 the fungus being retrieved from fallen
fruits of Liquidambar styraciflua L. collected in eastern
North America.7 The structure of 1 was determined using
NMR spectroscopy, and the absolute configuration was
not assigned. It was demonstrated that xylarenals are
selective ligands for the NPY Y5 receptor, which accord-
ing to genetic and pharmacological studies is involved
in mediating food intake and body weight.8,9
In this paper, we describe the total synthesis of (+)-
xylarenal A (1), which constitutes the first synthetic entry
to an eremophilane sesquiterpene embodying a vinyl
aldehyde linked to the decalin ring skeleton and allows
the absolute configuration of xylarenal A to be estab-
lished. Additionally, the synthesis of 1R-hydroxyiso-
ondetianone,10 which is formed in the course of the
synthetic route to xylarenal A, is reported. This tri-
noreremophilane was isolated by Bohlmann from aerial
parts of Ondetia lineariz in 1989.
The total synthesis of the sesquiterpenoid xylarenal A is
reported. This first synthetic entry to an eremophilane
terpenoid with an exocyclic vinyl aldehyde unit involves the
use of the bicyclic enone (+)-3, which after a γ-oxidation and
R′-allylation leads to the formation of the ketone (+)-8. After
its acylation, an oxidative cleavage of the allyl side chain
followed by R-methylenation of the resulting aldehyde gives
(+)-xylarenal A (1). The synthesis of (-)-xylarenal A from
(-)-3 is also reported. Moreover, the first total synthesis of
the trinoreremophilane (+)-1R-hydroxyisoondetianone (5) is
described.
The rare eremophilane sesquiterpenoids1 embodying
the 8-oxo-9,11-eremophiladien-12-al motif2 are biogeneti-
cally related natural products that have been recently
isolated from Xylaria fungi (Figure 1). A total synthesis
of these novel sesquiterpenoids, which show noteworthy
pharmacological activities such as an HIV-1 integrase
inhibition (integric acid),3 NPY-receptor antagonism (xy-
larenals A and B),4 and cytotoxicity toward a CCRFCEM
leukemia line (eremophilane 07H239-A),5,6 has yet to be
reported.
Results and Discussion
Our synthetic planning (Figure 2) was based on the
use of the enantiopure bicyclic enone 311 as the advanced
(5) McDonald, L. A.; Barbieri, L. R.; Bernan, V. S.; Janso, J.; Lassota,
P.; Carter, G. T. J. Nat. Prod. 2004, 67, 1565-1567.
(6) For other eremophilane sesquiterpenes with the same vinylal-
dehyde unit (C11-C13) linked to the decalin ring, see: (a) 9-Oxoer-
emophila-10,11(13)-dien-12-al: Abell, A. D.; Massy-Westropp, R. A.
Aust. J. Chem. 1985, 38, 1263-1269. (b) Bipolaroxin: Sugawara, F.;
Strobel, G.; Fisher, L. E.; Van Duyne, G. D.; Clardy, J. Proc. Natl. Acad.
Sci. U.S.A. 1985, 82, 8291-8294. (c) Bipolal: Watanabe, N.; Fujita,
A.; Ban, N.; Yagi, A.; Etoh, H.; Ina, K.; Sakata, K. J. Nat. Prod. 1995,
58, 463-466. (d) KM-01: Kim, S.; Hatori, M.; Ojika, M.; Sakagami,
Y.; Marumo, S. Bioorg. Med. Chem. 1998, 6, 1975-1982. (e)
Sch420789: Puar, M. S.; Barrabee, E.; Hallade, M.; Patel, M. J.
Antibiot. 2000, 53, 837-838.
(1) For recent biosynthetic studies about eremophilane sesquiter-
penes, see: (a) Calvert, M. J.; Ashton, P. R.; Allemann, R. K. J. Am.
Chem. Soc. 2002, 124, 11636-11641. (b) Zhao, Y.; Schenk, D. J.;
Takahashi, S.; Chappell, J.; Coates, R. M. J. Org. Chem. 2004, 69,
7428-7435. (c) Felicetti, B.; Cane, D. E. J. Am. Chem. Soc. 2004, 126,
7212-7221.
(2) Numbering according to: Connolly, J. D.; Hill, R. A. Dictionary
of Terpenoids; Chapman & Hall: London, 1992.
(3) (a) Singh, S. B.; Zink, D.; Polishook, J.; Valentino, D.; Shafiee,
A.; Silverman, K.; Felock, P.; Teran, A.; Vilella, D.; Hazuda, D. J.;
Lingham, R. B. Tetrahedron Lett. 1999, 40, 8775-8779. (b) Singh, S.
B.; Felock, P.; Hazuda, D. J. Biorg. Med. Chem. Lett. 2000, 10, 235-
238.
(7) Rogers, J. D. Can. J. Bot. 1979, 57, 941-945.
(8) Gehlert, D. R. Neuropeptides 1999, 33, 329-338.
(9) For recent studies about the neuropeptide Y, see: Blum, C.;
Zheng, X.; de Lombaert, S. J. Med. Chem. 2004, 47, 2318-2325.
(10) Zdero, C.; Bohlmann, F. Phytochemistry 1989, 28, 1653-1660.
Terpene nomenclature, 1R-hydroxy-11,12,13-trinor-9-eremophilen-8-
one; systematic name, (4aR,5S,8S)-8-hydroxy-4a,5-dimethyl-4,4a,5,6,7,8-
hexahydronaphthalen-2(3H)-one.
(4) Smith, C. J.; Morin, N. R.; Bills, G. F.; Dombrowski, A. W.;
Salituro, G. M.; Smith, S. K.; Zhao, A.; MacNeil, D. J. J. Org. Chem.
2002, 67, 5001-5004
10.1021/jo0502450 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/02/2005
J. Org. Chem. 2005, 70, 3749-3752
3749

SCHEME 1. Synthesis of Xylarenal A
FIGURE 2. Proposed synthetic pathway to xylarenal A.
synthetic intermediate, which as well as ensuring a
known configuration for the two stereogenic centers at
C(4) and C(5)2 might also allow good stereocontrol in the
genesis of the stereogenic centers at C(1) and C(7). As
starting material for the synthesis of target 1, shown in
Scheme 1, we used the (+)-Wieland-Miescher ketone 2,12
which is available from 2-methyl-1,3-cyclohexanedione
by an asymmetric process promoted by L-proline. Fol-
lowing the protocol developed by Paquette13 allowed the
building block 2, which has been widely used in the
synthesis of terpenoids and steroids, to be transformed
in a six-step sequence into the bicyclic enone (+)-3,14
which is the common intermediate for the syntheses
reported here (Scheme 1).
As the crucial steps in our approach to 1, we planned
an oxidation at C(1) to be followed by the formation of
the C(7)-C(11) bond, incorporating a latent acetaldehyde
side chain. Oxidation of 3 to install the hydroxyl group
at C(1) was carried out through its dienol ether (not
shown), which was treated by oxone under the conditions
reported by Fuchs in the steroid field.15,16 The stereo-
chemical outcome of this oxidation (Scheme 2), which
furnished the axial alcohol 4 (58%) and its equatorial
epimer 5 (14%),17 is consistent with that observed in
closely related systems.18 The configuration of alcohols
4 and 5 was assigned on the basis of the coupling pattern/
chemical shift observed for methine protons at C(1) and
C(9): axial alcohol 4 displays signals at δ 4.31 (t, J ) 3
Hz) and 5.81, respectively, while the equatorial alcohol
shows the two signals at δ 4.30 (ddd, J ) 11.5, 5.6, 1.9
Hz) and 6.19. Compared to its epimer, the latter is
deshielded due to the anisotropic effect of the near
hydroxyl group.
a Methyl vinyl ketone, L-proline. b(i) (CH2SH)2, TsOH; (ii)
Ph3PdCHOCH3, then HCl; (iii) NaBH4; (iv) MsCl; (v) LiBHEt3;
c
(vi) Tl(NO3)3. See Scheme 2.
(11) (4aR,5S)-Enantiomer was initially selected as an enantiopure
advanced precursor for biogenetic considerations, and later it was found
to be an adequate choice to build up the correct stereochemistry for 1.
(12) (a) Buchschacher, P.; Fu¨rst, A. Org. Synth. 1985, 63, 37-43.
(b) Harada, N.; Sugioka, T.; Uda, H.; Kuriki, T. Synthesis 1990, 53-
56.
SCHEME 2. Synthesis of
(+)-1-Hydroxyisoondetianone (5)
(13) Paquette, L. A.; Wang, T.-Z.; Philippo, C. M. G.; Wang, S. J.
Am. Chem. Soc. 1994, 116, 3367-3374
(14) For an alternative synthesis of (+)-3 from carvone, see: Ver-
stegen-Haaksma, A. A.; Swarts, H. J.; Jansen, B. J. M.; de Groot, A.
Tetrahedron 1994, 50, 10073-10082.
(15) Suryawanshi, S. N.; Fuchs, P. L. J. Org. Chem. 1986, 51, 902-
921 and references therein.
(16) For the γ-oxidation of enones through their methyl dienol ether
using m-CPBA, see: Kirk, D. N.; Wiles, J. M. J. Chem. Soc., Chem.
Commun. 1970, 1015-1016.
(17) Compounds 4 and 5 have been previously reported in the
racemic series from rac-3 via a rather lengthy route involving a six-
step sequence: Hagiwara, H.; Uda, H,; Kodama, T. J. Chem. Soc.,
Perkin Trans. 1 1980, 963-977.
(18) For the γ-hydroxylation of the 15-norderivative of rac-3, see:
(a) Holland, H.; Auret, B. Can. J. Chem. 1975, 53, 2041-2044. (b)
Wege, P. M.; Clark, R. D. Heathcock, C. H. J. Org. Chem. 1976, 41,
3144-3148. (c) Wijnberg, J.; Vader, J.; deGroot, A. J. Org. Chem. 1983,
48, 4380-4387. (d) Rubenstein, S. M.; Williams, R. M. J. Org. Chem.
1995, 60, 7215-7223.
Interestingly, the minor alcohol formed corresponds to
the trinorsesquiterpenoid 1R-hydroxyisoondetianone (5),10
1
whose H NMR and optical rotation data coincide fully
3750 J. Org. Chem., Vol. 70, No. 9, 2005

with those of the natural product, allowing the absolute
configuration of this terpenoid to be determined.17 This
natural product was obtained in a better yield by
converting its epimer, alcohol 4, into 5 through a Mit-
sunobu process,19 followed by a saponification of the
nitrophenylbenzoate initially formed.20 Thus, the overall
yield for the transformation of (+)-3 into (+)-5 is 54%
(Scheme 2).
FIGURE 3. Stereofigure of (+)-xylarenal A.
Returning to the synthetic sequence to xylarenal A, to
optimize the yield of the required alcohol 4, the minor
epimer 5 was converted to axial alcohol 4 using the above
Mitsunobu protocol with a 67% yield, thus increasing the
overall yield of the transformation (3 f 4) to 68%. Alcohol
4 was then protected with TBSCl, to give compound 6 in
84% yield. Treatment of the kinetic enolate of 621 with
allyl bromide diastereoselectively gave compound 7 in
55% yield (74% based on recovered ketone 6).22 After
removal of the TBS group from 7 using TBAF, alcohol 8
was isolated in 88% yield.23 The configuration at C(7) was
established by means of NOESY experiments, which
showed a strong cross-peak connecting H-7ax and the
C(14) methyl group. Moreover, the chemical shift (δ 18.3)
of C(14) is diagnostic of the equatorial disposition of the
allyl group from compound 7 onward.
At this point, we decided to examine the sequence in
reverse with an initial allylation at C(7) followed by an
oxidation at C(1) to avoid the protection/deprotection
steps.24 When the allylation process was carried out from
3, the conversion to ketone 10 was achieved in 52% yield,
the diallylated derivative being isolated in 12% yield.
However, the γ-oxidation now took place in only 34%
yield to give alcohol 8 together with 10% of its epimer at
C(1). So, although this sequence (3 f 8) only requires
two steps, its overall yield (17%) compared with that
obtained in the sequence depicted in Scheme 1 (29%) led
us to discard this protocol.
compound 11 being isolated in nearly quantitative yield.
The last phase of the xylarenal A synthesis implies the
oxidation of the allyl moiety to achieve aldehyde 12,
which should be submitted to a methylenation process.
While the ozonolysis cleavage of 11 was unsuccessful, the
catalytic OsO4 process, using 2,6-lutidine as an additive,25
led satisfactorily to aldehyde 12. Finally, the C(13)
methylene was installed in only one step by a reaction
of 12 with dimethyl methyleneammonium iodide (Es-
chenmoser’s salt) in CH2Cl2 and triethylamine as a
base,26,27 which proceeded smoothly to give 1 in 78% yield.
Compound 1 had NMR spectral data matching those
reported for the isolated xylarenal A,28 which allowed us
to conclude that the stereostructure of the natural
product corresponds to that of 1. The dextrorotatory
power of 1, [R]D + 28.2 (c 0.45, CH2Cl2), has enabled the
absolute configuration of the bicyclic core of xylarenal A
to be established as 1R,4S,5R,7S.29
In summary, the first synthesis of (+)-xylarenal A has
been accomplished (14 steps from (+)-Wieland-Miescher
ketone, 7% overall yield). The route here described is the
first to achieve sesquiterpenoids embodying an R,â-
unsaturated aldehyde moiety directly attached to the R′-
position of the bicyclic enone motif.30,31
Building on this approach, the synthetic entry to the
nonnatural enantiomer is also possible since the key
intermediate 3 is available in its levo form.32 Thus,
starting from (-)-3,33 which is obtained in 28% yield from
the commercially available (R)-3-methylcyclohexanone,
and following the same protocol described in Scheme 1,
We pursued the synthetic process by means of esteri-
fication of alcohol 8 with decanoic anhydride to achieve
the characteristic side chain of the target at C(1),
(25) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6,
3217-3219
(19) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017-
3020.
(26) Takano, S.; Inomata, K.; Samizu, K.; Tomita, S.; Yanase, M.;
Suzuki, M.; Iwabuchi, Y.; Sugihara, T.; Ogasawara, K. Chem. Lett.
1989, 1283-1284.
(20) For a related process, see: Lejeune, J.; Lallemand, J. Y.
Tetrahedron Lett. 1992, 33, 2977-2980.
(21) For R′-allylation of related bicyclic enones, see: (a) Zoretic, P.
A.; Ferrari, J. L.; Bhakta, C.; Barcelos, F.; Branchaud, B. J. Org. Chem.
1982, 47, 7, 1327-1329. (b) Bell, R. P.; Wijnberg, J.; de Groot, A. J.
Org. Chem. 2001, 66, 2350-2357.
(22) This yield was obtained working on a 0.4 mmol scale. Working
on a 4 mmol scale affords a slightly better yield (58%), but compound
7 is formed together with the diallylated derivative (not shown) in 25%
yield. These compounds are not easy to separate at this stage, but after
the deprotection step their corresponding alcohols can be separated.
(23) Deprotection of 7 using acidic conditions leads to the formation
of considerable amounts of the diketone 9.
(27) For some examples of this direct R-methylenation of aldehydes
in the natural product synthesis, see: (a) Nicolaou, K. C.; Reddy, K.
R.; Skokotas, G.; Sato, F.; Xiao, X.-Y.; Hwang, C.-K. J. Am. Chem. Soc.
1993, 115, 3558-3575. (b) Mizutani, H.; Watanabe, M.; Honda, T.
Tetrahedron 2002, 58, 8929-8936. (c) Lam, H. W.; Pattenden, G.
Angew. Chem., Int. Ed. 2002, 41, 508-511. (d) Smith, A. B., III;
Sfouggatakis, C.; Gotchev, D. B.; Shirakami, S.; Bauer, D.; Zhu, W.;
Doughty, V. A. Org. Lett. 2004, 6, 3637-3640.
(28) Due to the dearth of the natural product (personal communica-
tion of Dr. Cameron J. Smith, Merck & Co., Inc.), we were unable to
obtain a sample of natural xylarenal A. In the communication, it
became clear that xylarenal A is unstable on storage, even when kept
in the freezer.
(29) Xylarenal A: terpene name, 1-decyloxycarbonyl-8-oxo-9,11(13)-
eremophiladien-12-al; systematic name, (3S,4aR,5S,8R)-8-decyloxy-
carbonyl-3-[(1-formyl)vinyl]-4a,5-dimethyl-4,4a,5,6,7,8-hexahydronaph-
thalen-2(3H)-one.
(30) This structural motif is also found in the monoterpenoid
vesperal, which has been synthesized but through synthetic procedures
that are not easily applicable, if at all, to obtain 1. rac-Vesperal: Boyer,
F. D.; Malosse, C.; Zagatti, P.; Einhorn, J. Bull. Soc. Chim. Fr. 1997,
134, 757-764. (+)-Vesperal: Domon, K.; Mori, K. Eur. J. Org. Chem.
2000, 3787-3785. Fuganti, C.; Serra, S. Helv. Chim. Acta 2002, 85,
2489-2502.
(31) For the elaboration of a vinyl aldehyde side chain in the
eudesmane-type sesquiterpenes, see: Xiong, Z.; Yang, J.; Li, Y.
Tetrahedron: Asymmetry 1996, 7, 2607-2612.
(24)
J. Org. Chem, Vol. 70, No. 9, 2005 3751

SCHEME 3. Synthesis of (-)-Xylarenal A
Acknowledgment. Support of this research was
provided by the Spanish Ministry of Education and
Science (Project 2001BQU-3551). Thanks are also due
to the DURSI (Catalonia) for Grant 2001SGR-00083 and
pre- (S.D.) and postdoctoral (B.B.) fellowships.
Supporting Information Available: Experimental pro-
cedures and spectroscopic and analytical data for compounds
1 and 4-12, as well as 1H and 13C NMR copies for all reported
compounds, including COSY and HSQC spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO0502450
a (i) HCO2Et, NaOMe; (ii) PhNHMe; (iii) LDA, MeI; (iv)
Br(CH2)2CO2Et, Kt-BuO; (v) 1 N HCl, THF, then 1 N NaOH; (vi)
NaOAc, Ac2O; (vii) (MeO)2POMe, BuLi.
(32) Cuesta, X.; Gonza´lez, A.; Bonjoch, J. Tetrahedron: Asymmetry
1999, 10, 3365-3370. For another synthesis of (-)-3, see: Schenato,
R. A.; dos Santos, E. M.; Tenius, B. S. M.; Costa, P. R. R.; Caracelli, I.;
Zukerman-Schpector, J. Tetrahedron: Asymmetry 2001, 12, 579-584.
(33) We have prepared (-)-3 by our procedure (ref 32) with some
improvements: D´ıaz, S.; Cuesta, J.; Gonza´lez, A.; Bonjoch, J. J. Org.
Chem. 2003, 68, 7400-7406. The overall yield (28%) is the same as
that obtained with Paquette’s procedure (ref 13) using the (-)-
Wieland-Miescher ketone.
we have arrived at (-)-xylarenal A, [R]D -32.7 (c 0.85,
CH2Cl2) (Scheme 3).
3752 J. Org. Chem., Vol. 70, No. 9, 2005