Total synthesis of jatrophane diterpenes from euphorbia characias

Article abstract of DOI:10.1021/ol900819u

The enantioselective total synthesis of the jatrophane diterpene (-)-15-0-acetyl-3-O-propionylcharaciol is described. Starting from an advanced cyclopentane building block, a B-alkyl Suzuki-Miyaura cross-coupling and carbonyl addition were utilized to ass

Full text of DOI:10.1021/ol900819u

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2555-2558
Total Synthesis of Jatrophane
Diterpenes from Euphorbia characias†
Christoph Schnabel and Martin Hiersemann*
Fakulta¨t Chemie, Technische UniVersita¨t Dortmund, 44227 Dortmund, Germany
martin.hiersemann@tu-dortmund.de
Received April 15, 2009
ABSTRACT
The enantioselective total synthesis of the jatrophane diterpene (-)-15-O-acetyl-3-O-propionylcharaciol is described. Starting from an advanced
cyclopentane building block, a B-alkyl Suzuki-Miyaura cross-coupling and carbonyl addition were utilized to assemble a fully functionalized
triene, and a ring-closing metathesis was then employed to construct the rigid 12-membered ring. Twenty-five years after the original report
on the isolation of the natural product, our total synthesis unambiguously corroborates the original tentative structural assignment.
Jatrophane diterpenes have been isolated in great structural
diversity from plants of the genus Euphorbia.1 Members of
the jatrophane family of diterpenes are characterized by a
highly oxygenated trans-bicylo[10.3.0]pentadecane scaffold
and display a wide range of biological activities2 such as
multidrug resistance modulating properties3 and cytotoxicity
against human cancer cell lines.4
Progress toward the total synthesis of jatrophanes from
Euphorbia plants has been made recently, but to date no total
synthesis has been reported.5,6
In 1984, Seip and Hecker reported the isolation of the
∆5,6∆12,13 jatrophane 2 from Euphorbia characias (Figure
1).7 The structure of 2 was assigned based on 1H NMR (90
† Dedicated to Prof. Dr. Hans-Ulrich Reiꢀig on the occasion of his 60th
birthday.
(1) Shi, Q.-W.; Su, X.-H.; Kiyota, H. Chem. ReV. 2008, 108, 4295–
4327.
(2) Barile, E.; Corea, G.; Lanzotti, V. Nat. Prod. Commun. 2008, 6,
1003–1020.
(3) Corea, G.; Fattorusso, E.; Lanzotti, V.; Motti, R.; Simon, P.-N.;
Dumontet, C.; Di Pietro, A. J. Med. Chem. 2004, 47, 988–992.
(4) (a) Molnar, J.; Gyemant, N.; Tanaka, M.; Hohmann, J.; Bergmann-
Leitner, E.; Molnar, P.; Deli, J.; Didiziapetris, R.; Ferreira, M. J. U. Curr.
Pharm. Res. 2006, 12, 287–311. (b) Valente, C.; Pedro, M.; Ascenso, J. R.;
Abreu, P. M.; Nascimento, M. S. J.; Ferreira, M.-J. U. Planta Med. 2004,
70, 244–249.
Figure 1. Jatrophane framework (1) and the proposed structure of
the jatrophane diterpene 2 from Euphorbia characias. Jatrophane
numbering is used throughout the manuscript.
(5) For synthetic efforts toward jatrophane diterpenes from Euphorbia
sp., see: (a) Helmboldt, H.; Rehbein, J.; Hiersemann, M. Tetrahedron Lett.
2004, 45, 289–292. (b) Gilbert, M. W.; Galkina, A.; Mulzer, J. Synlett 2004,
2558-2562. (c) Mulzer, J.; Giester, G.; Gilbert, M. HelV. Chim. Acta 2005,
88, 1560–1579. (d) Helmboldt, H.; Ko¨hler, D.; Hiersemann, M. Org. Lett.
2006, 8, 1573–1576. (e) Shimokawa, K.; Takamura, H.; Uemura, D.
Tetrahedron Lett. 2007, 48, 5623–5625. (f) Helmboldt, H.; Hiersemann,
M. J. Org. Chem. 2009, 74, 1698–1708.
MHz) spectroscopy, mass spectrometry, and in analogy to
structurally related lathyrane diterpenes from E. characias.
However, the position of the acyl moieties was only
tentatively assigned due to “a lack of material”. Herein, we
10.1021/ol900819u CCC: $40.75
Published on Web 05/19/2009
 2009 American Chemical Society

describe our studies on the total synthesis of 15-O-acetyl-
3-O-propionylcharaciol (2) which culminated in the first total
synthesis of this natural product and verified the original
structural assignment by Seip and Hecker.
From a retrosynthetic perspective, we considered the diol
3, named characiol by Seip and Hecker, as an obvious
intermediate for the synthesis of the diester 2 and planned
to disassemble the rigid 12-membered ring of 3 using a ring-
closing metathesis (RCM) transform and a cross-coupling
transform (Figure 2). This approach considered previous
convert 6 to the alkyne 7. Thus, olefination8 of the aldehyde
6 provided a dibromoolefin that was treated with an excess
of methyllithium9 to afford the corresponding lithium acetyl-
ide which was in turn reacted in situ with methyliodide to
furnish the alkyne 7. Finally, the targeted vinyl iodide 8
emerged as a single double bond isomer through hydrozir-
conation10 of the alkyne 7 and subsequent exposure of the
intermediate vinyl zirconium species to iodine.
We next turned our attention to the synthesis of the cross-
coupling partner 5 for the vinyl iodide 8 (Scheme 2).
Scheme 2
Figure 2. Retrosynthetic analysis of characiol (3).
futile attempts to employ a RCM for the construction of the
C5/C6 double bond.5d,f Accordingly, the highly substituted
cylopentane segment of 3 would be derived from the building
block 4, for which a scalable access has already been
developed.5d,f Furthermore, the appropriately functionalized
olefin 5, containing a latent C12/C12′ double bond for the
planned RCM, was envisaged as the C7-C12 synthon.
The conversion of the building block 4 to the vinyl iodide
8 that is required for the cross-coupling with the C7-C12
synthon 5 was realized according to Scheme 1. Reduction
Dibromide 911 was treated with an in situ generated
phenylselenide anion equivalent12 to provide the bromide
1013 which was subsequently used for the alkylation of the
enolate of isobutyronitrile to deliver the nitrile 11. Nitrile
11 was then reduced to the aldehyde 12 which was exposed
to vinylmagnesium bromide to furnish the allylic alcohol 13.
In light of the envisioned synthetic sequence ahead of us,
we opted for the introduction of a PMB ether as a protecting
group14 for the allylic hydroxyl group in 13. Overall, the
Scheme 1
(6) For total syntheses of jatrophone, a jatrophane diterpene from
Jatropha gossypiifolia, see: (a) Smith, A. B.; Lupo, A. T.; Ohba, M.; Chen,
K. J. Am. Chem. Soc. 1989, 111, 6648–6656. (b) Gyorkos, A. C.; Stille,
J. K.; Hegedus, L. S. J. Am. Chem. Soc. 1990, 112, 8465–8472. (c) Han,
Q.; Wiemer, D. F. J. Am. Chem. Soc. 1992, 114, 7692–7697.
(7) Seip, E. H.; Hecker, E. Phytochemistry 1984, 23, 1689–1694.
(8) Desai, N. B.; McKelvie, N.; Ramirez, F. J. Am. Chem. Soc. 1962,
84, 1745–1747.
(9) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769–3772.
(10) (a) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115–
8116. (b) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem. Soc.
1975, 97, 679–680.
(11) Middleton, D. S.; Simpkins, N. S.; J Begley, M.; K Terrett, N.
Tetrahedron 1990, 46, 545–564.
(12) Liotta, D.; Markiewicz, W.; Santiesteban, H. Tetrahedron Lett.
1977, 18, 4365–4367. We are grateful to a reviewer for bringing this work
to our attention.
of the methyl ester 4 and acetalization of the resulting diol
were followed by the oxidative cleavage of the double bond
to provide the aldehyde 6 which could be purified by
chromatography. A two-step procedure was utilized to
(13) For the synthesis of the corresponding iodide, see: Baldwin, J. E.;
Adlington, R. M.; Robertson, J. Tetrahedron 1989, 45, 909–922.
(14) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139–4142.
2556
Org. Lett., Vol. 11, No. 12, 2009

C7-C12 building block (()-5 was synthesized in five steps
and 47% yield using commercially available substrates and
reagents.
Having achieved the synthesis of the vinyl iodide 8 and
the olefin 5, attention was turned toward the fusion of these
building blocks (Scheme 3). A B-alkyl Suzuki-Miyaura
and Brønsted acids, it was determined that the removal of
the isopropylidene protecting group was most effectively
accomplished using La(NO3)3 hexahydrate in acetonitrile at
elevated temperatures.18 The resulting diol was subsequently
oxidized with IBX to provide the aldehyde 15 as a mixture
of C9 diastereomers.19 The stage was now set for the
introduction of the remaining carbon atoms. Nucleophilic
addition of isopropenyl lithium, generated in situ by
halogen-lithium exchange,20 to the R-hydroxy aldehyde 15
furnished the corresponding diol. Oxidative removal of the
PMB group with DDQ21 gave the corresponding triol, and
subsequent oxidation of the C9 and C14 hydroxyl groups
provided the diketone 16.
Scheme 3
With triene 16 in hand, we proceeded to study the key
RCM step for the formation of the 12-membered ring.
Gratifyingly, exposure of 16 to Grubbs’ second-generation
metathesis catalyst 1722 (0.1 equiv) in refluxing toluene
delivered the desired bicyclic product contaminated with
inseparable impurities. The byproduct from the RCM could
be removed subsequently to the cleavage of the remaining
TBS protecting group with HF in pyridine to deliver 3-epi-
characiol (18) in 44% isolated yield from the triene 16.
Finally, a stereospecific Mitsunobu reaction23 and a subse-
quent transesterification of the resulting para-bromo benzoic
acid ester converted 3-epi-characiol (18) to characiol (3).
With the jatrophane core in place, the final task was the
regioselective esterification of characiol (3) (Scheme 4).
Scheme 4
cross-coupling15 reaction under the conditions originally
described by Johnson and Braun16 delivered the olefin 14
as a mixture of C9 diastereomers. Subsequent oxidation of
the selenide to the selenoxide triggered an elimination that
furnished the C12/C12′ double bond required for the RCM.17
We next faced the challenge of cleaving the isopropylidene
acetal in the presence of the TBS and the PMB protecting
groups. After substantial experimentation with various Lewis
Because of the uncertainties in the structural assignment of
the natural product, the synthesis of the two regioisomeric
diesters 2 and 21 was desirable. Thus, upon treating characiol
(3) with an excess of propionic acid, EDC,24 and DMAP,
(15) Miyaura, N.; Ishiyama, T.; Ishikawa, M.; Suzuki, A. Tetrahedron
Lett. 1986, 27, 6369–6372.
(18) Reddy, S. M.; Reddy, Y. V.; Venkateswarlu, Y. Tetrahedron Lett.
2005, 46, 7439–7441.
(16) (a) Johnson, C. R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115,
11014–11015. For Ph3As, see: (b) Farina, V.; Krishnan, B. J. Am. Chem.
Soc. 1991, 113, 9585–9595.
(19) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019–
8022.
(17) (a) Jones, D. N.; Mundy, D.; Whitehouse, R. D. J. Chem. Soc.
1970, 86-87. (b) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40,
947–949.
(20) (a) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404–
5406. (b) Negishi, E.; Swanson, D. R.; Rousset, C. J. J. Org. Chem. 1990,
55, 5406–5409.
Org. Lett., Vol. 11, No. 12, 2009
2557

3-O-propionylcharaciol (19) was isolated and subsequently
converted to 15-O-acetyl-3-O-propionylcharaciol (2) under
conditions described by Procopiou et al.25 In an analogous
fashion, 3-O-acetyl-15-O-propionylcharaciol (21) was ac-
plants of the genus Euphorbia. The synthesis we have
delineated demonstrates the potential of a strategy involving
B-alkyl Suzuki-Miyaura cross-coupling and ring-closing
metathesis for the assembling of the rigid trans-
bicyclo[10.3.0]pentadecane core of jatropha-5,12-dienes. The
possibility of adapting the established strategy to the synthesis
of other members of the jatrophane family of diterpenes is
currently under investigation.
1
cessed via 3-O-acetylcharaciol (20). Comparison of the H
NMR data of the natural product and the synthetic diesters
2 and 21 unambiguously corroborates the original structural
assignment by Seip and Hecker.7
In summary, we have accomplished the first enantiose-
lective total synthesis of a jatrophane diterpene (2) from
Acknowledgment. Financial support of this work was
provided by the Deutsche Forschungsgemeinschaft (HI 628/
6).
(21) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885–888.
(22) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
Supporting Information Available: Experimental pro-
1, 953–956.
(23) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380–
2382.
cedures, spectral and analytical data for new compounds,
1
and copies of H and 13C NMR spectra. This material is
(24) Sheehan, J.; Cruickshank, P.; Boshart, G. J. Org. Chem. 1961, 26,
2525–2528.
available free of charge via the Internet at http://pubs.acs.org.
(25) Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G. G. A. J.
Org. Chem. 1998, 63, 2342–2347.
OL900819U
2558
Org. Lett., Vol. 11, No. 12, 2009