The first total synthesis of xenitorins B and C: Assignment of absolute configuration

Article abstract of DOI:10.1039/b610427d

The first total synthesis of xenitorins B(1) and C(2) in natural form, which serves to confirm the structural assignments, establish the absolute stereochemistry and provide an easy access to the interesting marine sesquiterpenes was analyzed. The synthetic design calls for the use of optically active βpinene(3) both as the the starting substrate and source of chirality and its derivative 4 to facilitate the construction of the core system via a Diels-Alder reaction. This is followed by an acid catalyzed fragmentation process after suitable modifications. Formylation of (+)-7 followed by treatment of the resulting a-hydroxymethylene ketone with hydroxykamine gave rise to isoxazole(-)-9. The identity of the synthetic compounds and the corresponding natural products was established by direct comparison of their H nmr spectra. Result shows that B (-)1 and C(-)2 has been achieved and served to establish the absolute configuration of these structurally interesting natural products.

Full text of DOI:10.1039/b610427d

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The first total synthesis of xenitorins B and C: assignment of absolute
configuration†
Wen-Sheng Chang,a Kak-Shan Shia,a Hsing-Jang Liu*a and Tai Wei Lyb
Received 20th July 2006, Accepted 31st August 2006
First published as an Advance Article on the web 8th September 2006
DOI: 10.1039/b610427d
Starting from (−)-b-pinene, the first total synthesis of xeni-
torins B and C has been accomplished, which also allowed
the assignment of their absolute configuration.
which is known to be quite hazardous, and several severe explo-
sions were experienced in the past during its application.4 In light
of this, a more secure procedure was employed using ruthenium(III)
chloride (0.023 equiv.) and sodium periodate (2.1 equiv.)5 in
aqueous acetonitrile and carbon tetrachloride. (+)-Nopinone
((+)-7) thus obtained in 81% yield was subsequently converted to
the desired dienophile 4 in the following manner. The introduction
of the required cyano group was effected using a well established
isoxazole rearrangement protocol.6,7 Thus, formylation of (+)-7
followed by treatment of the resulting a-hydroxymethylene ketone
(+)-83,8 with hydroxylamine gave rise to isoxazole (−)-9, which was
subjected to base-induced rearrangement using sodium ethoxide
to afford cyano ketone (+)-10, which was found to exist completely
in the keto form at room temperature. The dienophilic double bond
was subsequently incorporated using the phenylselenenylation-
oxidative elimination process9 to furnish cyano enone (+)-4 in
65% overall yield from (+)-7.
In 2002, Duh et al. reported the isolation, from the soft coral
Xenia Puerto-galerae Roxas collected off the shore of Green
Island near Taiwan, of a series of cytotoxic new cadinanoids
coined xenitorins, including xenitorins B (1) and C (2).1 The
structures of these compounds, including relative stereochemistry,
were deduced on the basis of extensive spectroscopic studies.1
Their absolute configuration was, however, unresolved. Herein
we wish to report the first total synthesis of xenitorins B (1)
and C (2) in natural form, which serves to confirm the structural
assignments, establish the absolute stereochemistry, and provide
an easy access to these interesting marine sesquiterpenes.
As depicted in the retrosynthetic scheme (Scheme 1), our
synthetic design calls for the use of optically active b-pinene
(3) both as the starting substrate and source of chirality and its
derivative 4 to facilitate the construction of the core system via a
Diels–Alder reaction (4 → 5). This is followed by an acid catalyzed
fragmentation process2 after suitable modifications (5 → 6).
Scheme 2
Scheme 1
Cyano enone (+)-4 proved to be an effective dienophile. Its
Diels–Alder reaction with isoprene, carried out at room temper-
ature in methylene chloride in the presence of zinc chloride,10
proceeded with a high degree of efficiency and a completely
regio- and stereoselective manner to give adduct (+)-5 as the
sole product in 84% yield (Scheme 3). After serving as an
activating group for the Diels–Alder reaction, the angular cyano
moiety in (+)-5 was readily removed by applying a reductive
decyanation process developed previously in our laboratories.11–14
Thus, treatment of (+)-5 with lithium naphthalenide (LN)15 in
dry tetrahydrofuran followed by protonation gave rise to an 86%
yield of enone (−)-1116 as a single product, the stereochemistry
of which was suggested by NOE experiments showing no effect
The experimental work† began with the conversion of (−)-b-
pinene ((−)-3) to (+)-nopinone ((+)-7) (Scheme 2). The traditional
method to effect this operation involves ozonolysis,3 a process
aDepartment of Chemistry, National Tsing Hua University, Hsinchu, 30013,
Taiwan, R. O. C. E-mail: hjliu@mx.nthu.edu.tw; Fax: +886-3-572-0711;
Tel: +886-3-573-4292
bActimis Pharmaceuticals, Inc. 11099 N. Torrey Pines Rd. Suite 200, La
Jolla, CA, 92037, USA. E-mail: twly@actimis.com; Fax: +1-858-678-8576;
Tel: +1-858-678-8567
† Electronic supplementary information (ESI) available: Experimental
procedures and spectral characterizations for compounds 1, 2, 4, 5, 6,
9, 10, 12, 14, 17–19 are provided. See DOI: 10.1039/b610427d
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Scheme 3
Scheme 5
between the fused-ring junction hydrogen atoms. Enone (−)-11
was subsequently subjected to catalytic hydrogenation using 20%
palladium-on-carbon to saturate the olefinic double bond. The
reaction proceeded smoothly, but unfortunately produced an
intractable mixture of the desired isomer (+)-1217 (vide infra) and
its epimer 13 in a 2 : 1 ratio.
To circumvent this problem, (+)-5 was subjected to hydrogena-
tion prior to the removal of the cyano group (Scheme 4), which
proved to be highly satisfactory. Catalytic hydrogenation of (+)-5
in ethanol using 20% Pd/C under 30 psi of hydrogen gave rise
to a 91% yield of the desired isomer (+)-14 as the only product,
the configuration of the newly generated stereogenic center was
confirmed at a later stage (vide infra). Reductive decyanation
of (+)-14 was then performed using LN as the reducing agent,
resulting in the formation of ketone (+)-12 (86% yield). This
compound didn’t display any NOE effect between the fused-ring
junction hydrogen atoms.
and 16, which, upon further treatment with a small amount of
p-toluenesulfonic acid in refluxing aqueous acetone, gave trans-
ketone (−)-6 and its cis-isomer (+)-17 in 3 : 2 ratio and a
combined yield of 93% over two steps. These diastereomers were
separated, and the relative stereochemistry of the trans-isomer
(−)-6 was unambiguously established by X-ray analysis18,19‡ while
the presumed cis-isomer (+)-17 was treated with sodium hydroxide
in refluxing methanol to furnish (−)-6 as the predominant product.
Towards xenitorin C (2), ketone (−)-6 was sequentially treated with
lithium diisopropylamide and diphenyl diselenide (Scheme 6).20
This was immediately followed by oxidative elimination of the
ensuing phenylselenenyl intermediate using hydrogen peroxide
to give enone (−)-18 which, on exposure to methyllithium in
tetrahydrofuran at 0 ◦C in the presence of cerium(III) chloride,21,22
gave rise to xenitorin C ((−)-2) in 34% yield along with a 58% yield
of its epimer 19. It was somewhat disappointing that the desired
compound (−)-2 was consistently produced in a lesser amount
regardless of the reaction conditions and the reagents applied,
as a consequence of the preferential axial addition leading to
the undesired stereochemistry. As a small consolation, however,
both isomers (−)-2 and 19 were readily converted to xenitorin
B ((−)-1) in 69% and 73% yield, respectively, upon treatment
with pyridinium chlorochromate on Celite23 in methylene chloride
(Scheme 7). The identity of the synthetic compounds and the
corresponding natural products was established by direct compar-
1
ison of their H nmr spectra.1 As well, other spectral data and
physical properties, including specific rotations of the synthetic
Scheme 4
To complete the core system of the target compounds from
(+)-12, it remains to selectively cleave the cyclobutane bond
linking the quaternary center and the carbon a to the carbonyl.
In a previous investigation,2 it was serendipitously observed that
this type of ring cleavage could be effectively achieved under
standard ketalization conditions. Accordingly, ketone (+)-12 was
treated with ethylene glycol and p-toluenesulfonic acid in refluxing
benzene with azeotropic removal of water (Scheme 5). Indeed,
the desired fragmentation occurred with concomitant ketalization
and partial isomerization to give a mixture of epimeric ketals 15
Scheme 6
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17 Compound 12 has been previously reported by this research group (see
ref. 16b).
Scheme 7
materials, were also shown to be in excellent agreement with
those reported for the naturally occurring compounds.1 Thus,
the first total synthesis of xenitorins B ((−)-1) and C ((−)-2) has
been achieved and serves to unambiguously establish the absolute
configuration of these structurally interesting natural products.
Acknowledgements
18 Crystal structure data for (−)-6 has been deposited with the
Cambridge Crystallographic Data Centre and allocated the depo-
sition number CCDC 602444. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
We are grateful to the National Science Council of the Republic
of China for financial support and to Professor C. Y. Duh of
National Sun Yat-Sen University for 1H nmr spectra of the natural
xenitorins B and C.
19 Chemical formula (C14H22O), formula weight (206.32), crystal system
˚
˚
(monoclinic), unit cell dimensions (a = 9.1809(18) A, b = 6.4336(12) A,
◦
◦
˚
c = 11.416(2) A, a = c = 90 , b = 108.320(4) ), unit cell volume
Notes and references
3
˚
(640.1(2) A ), Z = 2, temperature (294(2) K), space group (P2(1)),
absorption coefficient (0.065 mm−1), reflections collected (4800), inde-
pendent reflections including Friedel pairs (3005), Rint = 0.0500, R1 =
0.0441, wR2 = 0.0974 for observeddata, I > 2r(I). No conclusion
pertaining to the absolute stereochemistry of (−)-6 is drawn from this
X-ray analysis.
‡ CCDC reference numbers 602444. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b610427d
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The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3751–3753 | 3753
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