Concise total synthesis of spirocurcasone

Article abstract of DOI:10.1021/ol400228v

A concise total synthesis of spirocurcasone was accomplished. Key features of the synthesis involved a vinylogous Mukaiyama aldol reaction, a Carroll rearrangement of β-keto allyl ester derivative, an intramolecular aldol condensation, and a spiro ring fo

Full text of DOI:10.1021/ol400228v

ORGANIC
LETTERS
2013
Vol. 15, No. 6
1298–1301
Concise Total Synthesis
of Spirocurcasone
Hideki Abe, Akimi Sato, Toyoharu Kobayashi, and Hisanaka Ito*
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
itohisa@toyaku.ac.jp
Received January 28, 2013
ABSTRACT
A concise total synthesis of spirocurcasone was accomplished. Key features of the synthesis involved a vinylogous Mukaiyama aldol reaction, a
Carroll rearrangement of β-keto allyl ester derivative, an intramolecular aldol condensation, and a spiro ring formation by ring-closing metathesis
of the pentaene compound. This synthetic work was complete in nine steps from (S)- or (R)-perillaldehyde without the use of protecting groups.
Interestingly, the optical rotation of the synthetic spirocurcasone was different from the reported value of the natural product.
The Jatropha genus of Euphorbiaceae is a rich source of
biologically active natural products.1 Jatropha curcas L. is
an oil-bearing shrub distributed throughout many Latin
American, Asian, and African countries and has been used
as a source of lamp oil and soap. This plant has attracted
attention recently because of the use of its seed as a
sustainable source for biodiesel fuel.
In 2011, Taglialatela-Scafati and co-workers reported
the isolation of spirocurcasone 1 from the root bark of
Jatropha curcas.2 The structure of 1, a tricyclic diterpenoid,
was established as the spirorhamnofolane skeleton
through analysis of 2D NMR spectra including COSY,
HMBC, and ROESY experiments as depicted in Figure 1.
In addition, its absolute configuration was determined by
quantum mechanical ECD calculations.3 Related tricyclic
Figure 1. Structures of spirocurcasone, 1, and curcusones AꢀE,
diterpenoids curcasones AꢀE, 2ꢀ6,4 which exhibit anti-
2ꢀ6.
proliferative activity toward the mouse lymphoma
L5178Y cell line, were isolated along with spirocurcasone.
(ꢀ)-spirocurcasone in nine steps, involving four key reac-
tions: the vinylogous Mukaiyama aldol reaction, Carroll
rearrangement, intramolecular aldol condensation, and
ring-closing metathesis.
The synthetic plan for spirocurcasone 1 is outlined in
Scheme 1. The target molecule 1 would be obtained by
applying ring-closing metathesis to spiro ring system for-
mation from compound 7, which would be derived from
bicyclic enone 8 by acylation of the ketone, followed by
stereoselective allylation of the resulting diketone. The
This report describes the concise total synthesis of (þ)- and
(1) (a) Devappa, R. K.; Makkar, H. P. S.; Becker, K. J. Am. Oil
Chem. Soc. 2011, 88, 301. (b) Zhang, X.-P.; Zhang, M.-L.; Su, X.-H.;
Huo, C.-H.; Gu, Y.-C.; Shi, Q.-W. Chem. Biodiversity 2009, 6, 2166.
(2) Chianese, G.; Fattorusso, E.; Aiyelaagbe, O. O.; Luciano, P.;
€
€
Schroder, H. C.; Muller, W. E. G.; Taglialatela-Scafati, O. Org. Lett.
2011, 13, 316.
(3) Stephens, P. J.; Pan, J. J.; Devlin, F. J.; Krohn, K.; Kurtan, T.
ꢀ
J. Org. Chem. 2007, 72, 3521.
(4) Naengchomnong, W.; Thebtaranonth, Y.; Wiriyachitra, P.;
Okamoto, K. T.; Clardy, J. Tetrahedron Lett. 1986, 27, 2439.
r
10.1021/ol400228v
Published on Web 02/28/2013
2013 American Chemical Society

trans-bicyclic enone 8 would be constructed by intramole-
cular aldol condensation of 2-oxobutyl derivative 9 pro-
duced by a Carroll rearrangement reaction of the β-keto
allyl ester 10. The Carroll rearrangement precursor 10 can
be prepared from (R)-perillaldehyde (12) in four steps
including vinylogous Mukaiyama aldol reaction of the
silyl dienol ether with trialkyl orthoformate to produce
acetal derivative 11. To realize the goal, the attempt to
synthesize spirocurcasone began with (S)-perillaldehyde as
the starting material because it is less expensive than the
(R)-form.
Scheme 2. Synthesis of the Key Compound ent-18
Scheme 1. Synthetic Plan for Spirocurcasone, 1
Transformation of the allyl alcohol ent-15 to the β-keto
allyl esterent-16was performedby treatment ofent-15with
ethyl 3-oxovalerate and 4-dimethylaminopyridine in re-
fluxing toluene7 to give the Carroll rearrangement precur-
sor ent-16 in 91% yield, as shown in Scheme 2. Among the
many conditionsevaluatedfor the Carrollrearrangement,8
use of LDA as a base in cyclopentyl methyl ether (CPME)9
as a solvent gave the best result. After treatment with LDA
(3.0 equiv) in CPME at ꢀ78 °C, the reaction mixture of the
resulting lithium dienolate intermediate ent-17 in CPME
was refluxed for 20 h. The target R-2-oxobutyl compound
ent-18 and the undesirable β-2-oxobutyl product ent-19
were obtained in 46% and 15% yield, respectively. Re-
arrangement of the enolate anion from the C1 to the C2
position proceeded mainly from the opposite face of the
diethyl acetal group at C3, followed by decarboxylation to
produce the R-product ent-18 in 46% yield as the major
rearranged product.
The investigation began by preparing allyl alcohol ent-
15 using the stereoselective vinylogous Mukaiyama aldol
reaction5 as shown in Scheme 2. The TBS dienol ether ent-
13,6 the precursor for the vinylogous Mukaiyama aldol
reaction, was obtained easily in 99% yield by treatment of
(S)-perillaldehyde 12 with TBSOTf and triethylamine. The
vinylogous Mukaiyama aldol reaction of the TBS dienol
ether ent-13 with triethyl orthoformate as an aldol reaction
acceptor and BF3 OEt2 as a Lewis acid proceeded
3
smoothly to afford the diethyl acetal derivative ent-14 in
75% yield as a single diastereomer.
Reduction of the aldehyde group of ent-14 with DI-
BALH atꢀ78°C gavethe allyl alcoholent-15in93% yield.
(5) For recent reviews of the vinylogous Mukaiyama aldol reaction,
see: (a) Bisai, V. Synthesis 2012, 44, 1453. (b) Casiraghi, G.; Battistini, L.;
Curti, C.; Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076. (c)
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev.
2000, 100, 1929.
(6) (a) Siegel, C.; Gordon, P. M.; Uliss, D. B.; Handrick, G. R.;
Dalzell, H. C.; Razdan, R. K. J. Org. Chem. 1991, 56, 6865. (b) Tius,
M. A.; Gu, X.-Q.; Kerr, M. A. J. Chem. Soc., Chem. Commun. 1989, 62.
(7) Uneyama, H.; Niwa, S.; Onishi, T. U.S. patent, US6350766 B1,
2002.
(8) For a recent review of the Carroll rearrangement reaction, see:
Castro, A. M. M. Chem. Rev. 2004, 104, 2939.
(9) When using THF as the reaction solvent, the allyl alcohol 15 was
obtained along with the recovered starting compound 16.
Org. Lett., Vol. 15, No. 6, 2013
1299

With the desired ent-18 synthesized, the next goal was
construction of the tricyclic spiro fragment including the
bicyclic enone moiety to complete the target molecule.
Construction of the bicyclic enone moiety, which is an
integral component of the target compound, was per-
formed by intramolecular aldol condensation of the ob-
tained ent-18 under acidic conditions (conc. H2SO4, THF)
to give the enone ent-8 in 76% yield as shown in Scheme 3.
Fortunately, recrystallization of the enone ent-8 gave a
single crystal, so the stereochemistry of ent-8 could be
determinedunambiguously byX-ray crystallographic ana-
lysis as 4aR,5S,8aS.10 These results confirmed that the
Carroll rearrangement of ent-16 proceeded from the R face
as shown in Scheme 2 to afford ent-18 as the major
product. To stereoselectively introduce the two side chains
at the C1 position in ent-8, R acylation of ent-8 occurred
first. Treatment of enone ent-8 with LDA (2 equiv) and
methacryloyl chloride (3 equiv) at ꢀ78 °C gave the
R-acylated product in 70% yield. Stereoselective allylation
of the resulting β-diketone with potassium tert-butoxide
(2 equiv) and allyl iodide (4 equiv) in THF afforded the
pentaene derivative ent-7 in 70% yield as a single diaster-
eomer, which was the precursor to the spiro ring skeleton.
Stereochemistry of the resulting ent-7 was confirmed by
extensive spectroscopic analysis including NOESY experi-
ments at 600 MHz. Selected NOESY correlations of ent-7
are presented in Scheme 3. Clear NOE interactions be-
tween H8a and both H5 and the methyl group on the
methacryloyl group at C1 and between H4a to both the
allylic proton ontheallyl group atC1and the methylgroup
on the isopropenyl group at C5 were observed, indicating
that the stereochemical relation between the methacryloyl
group at C1 and the bridgehead proton at C8a was syn and
thatthe relationofthe allyl group atC1and the bridgehead
proton at C4a and the isopropenyl group at C5 were both
syn. Finally, ring-closing metathesis11 of the pentaene
compound ent-7 with the second-generation Grubbs cata-
lyst in CH2Cl2 at room temperature for 3 h successfully
gave the target tricyclic compound spirocurcasone in high
yield (98%). Both 1H and 13C NMR spectra of the
synthetic ent-spirocurcasone ent-1 were identical with
those of natural spirosurcasone 1.2 However, interestingly,
the optical rotation of the synthetic sample was different
from the reported value of the natural product [synthetic
Scheme 3. Synthesis of (þ)-Spirocurcasone, ent-1
In addition, determination of the absolute configuration
of our synthetic compound by vibrational circular dichro-
ism (VCD)13 in combination with a quantum mechanics
calculation technique was carried out.14 Consequently, the
absolute configuration of our synthetic spirocurcasone
was assigned as 8R,9S,10R,14S, using the spirorhamnofo-
lane skeleton numbering system. Therefore, to confirm the
optical rotation of natural spirocurcasone, synthesis of the
natural enantiomer (R)-perillaldehyde [(R)-12] through
the established procedure was conducted as shown in
Scheme 4. Results showed that both the 1H and 13C
NMR spectra of synthetic spirocurcasone 1 were identical
with those of natural spirocurcasone 1,2 even though the
optical rotation of the synthetic sample was very different
from the value reported for the natural product [synthetic
Scheme 4. Synthesis of Natural Spirocurcasone 1
26
ent-1: [R]D þ146.0 (c 1.00, CHCl3); natural product 1:
[R]D þ3.5 (c 0.02, CHCl3)2]. Therefore, the stereochem-
26
istry of the synthetic sample ent-1 was assigned using 2D
NMR analysis at 600 MHz.12 These results also indicated
the same structure as that reported by Taglialatela-Scafati
and shown in Figure 1.2
(10) CCDC 900529 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. The structure determined from the X-ray crystallo-
graphic analysis is provided in the Supporting Information.
(11) For a recent review of the application of ring-closing metathesis
to the total synthesis of natural products, see: Nicolaou, K. C.; Bulger,
P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490.
(12) See Supporting Information.
1300
Org. Lett., Vol. 15, No. 6, 2013

24
1: [R]D ꢀ155.2 (c 1.00, CHCl3)] as well as thatofsynthetic
achieve the target molecule. Furthermore, this synthetic
route did not require the use of any protective groups. An
accurate value for the optical rotation and the absolute con-
figuration of synthetic spirocurcasone also were determined.
ent-spirocurcasone, ent-1. These results suggest that the
optical rotation value reported by Taglialatela-Scafati is
inaccurate due to impurities or another factor.
In conclusion, the concise total synthesis of (þ)-spiro-
curcasone (ent-1) and (ꢀ)-spirocurcasone (1) was achieved
in nine steps from (S)- and (R)-perillaldehyde starting
material, respectively. Key steps of this synthesis involved
a vinylogous Mukaiyama aldol reaction to introduce the
diethyl acetal moiety, a Carroll rearrangement of the
β-keto allyl ester 16 to ketone 18, an aldol condensation
for construction of the bicyclic compound 8, and a
ring-closing metathesis of the pentaene derivative to
Acknowledgment. This work was supported by Platform
for Drug Discovery, Informatics, and Structural Life Science
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan. We are grateful to Dr. Y. Hitotsuyanagi
and Mr. H. Fukaya for VCD spectral measurements.
Supporting Information Available. Detailed experimen-
tal procedures and spectral data, as well as copies of the
1H and 13C NMR spectra, IR data, and HRMS of all
compounds in the synthetic route, are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(13) For recent reviews of VCD spectroscopy, see: (a) He, Y.; Wang,
B.; Duker, R. K.; Nafie, L. A. Appl. Spectrosc. 2011, 65, 699. (b)
Ranjbar, B.; Gill, P. Chem. Biol. Drug Des. 2009, 74, 101. (c) Stephens,
P. J.; Devlin, F. J.; Pan, J.-J. Chirality 2008, 20, 643.
(14) A detailed comparison of the experimental VCD and IR spectra
for the synthetic sample with VCD and IR spectra predicted from DFT
calculations was described in the Supporting Information.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 6, 2013
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