Synthesis of the norjatrophane diterpene (-)-15-acetyl-3-propionyl-17- norcharaciol

Article abstract of DOI:10.1021/ol060115t

A scalable enantioselective synthesis of the nonnatural 17-norjatrophane diterpene 3-propionyl-15-acetyl-17-norcharaciol is described. Key C/C-connecting transformations are an Evans aldol reaction, an intramolecular carbonyl ene reaction, a Horner-Wadsworth-Emmons olefination, and a ring-closing metathesis for the formation of a 12-membered carbacycle.

Full text of DOI:10.1021/ol060115t

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1573-1576
Synthesis of the Norjatrophane
Diterpene ( )-15-Acetyl-3-propionyl-
17-norcharaciol
−
Hannes Helmboldt, Daniel Ko1
hler,†,‡ and Martin Hiersemann*,‡
Fachrichtung Chemie, Technische UniVersita¨t Dresden, D-01062 Dresden, Germany
martin.hiersemann@chemie.tu-dresden.de
Received January 15, 2006
ABSTRACT
A scalable enantioselective synthesis of the nonnatural 17-norjatrophane diterpene 3-propionyl-15-acetyl-17-norcharaciol is described. Key
C/C-connecting transformations are an Evans aldol reaction, an intramolecular carbonyl ene reaction, a Horner Wadsworth Emmons olefination,
and a ring-closing metathesis for the formation of a 12-membered carbacycle.
−
−
Plants of the genus Euphorbia are a rich source of biologi-
cally active bi- and polycyclic diterpenes.1 Besides daph-
nanes, tiglianes, ingenanes, and others, diterpenes featuring
the jatrophane framework 1 are being isolated in tremendous
structural diversity.2-4 Jatrophanes possess a variety of
different biological activities. Most notably, they are inhibi-
tors of the P-glycoprotein (Pgp),5 a membrane protein whose
major function is the active transport of amphiphatic xeno-
toxins out of the cytoplasm.6 It is assumed that the overex-
pression of the multidrug resistance protein 1 (MDR1) gene
that encodes for Pgp contributes to the resistance of cancer
cells against a broad spectrum of antineoplastic drugs.7
† Undergraduate research participant.
(3) For recent reports on the isolation and the pharmacological properties
of jatrophanes from Euphorbia, see: (a) Corea, G.; Fattorusso, C.;
Fattorusso, E.; Lanzotti, V. Tetrahedron 2005, 61, 4485-4494. (b) Zhang,
W.; Guo, Y.-W. Planta Med. 2005, 71, 283-286. (c) Pan, Q.; Ip, F. C. F.;
Ip, N. Y.; Zhu, H.-X.; Min, Z.-D. J. Nat. Prod. 2004, 67, 1548-1551. (d)
Valente, C.; Pedro, M.; Duarte, A.; Nascimento, M. S. J.; Abreu, P. M.;
Ferreira, M.-J. U. J. Nat. Prod. 2004, 67, 902-904. (e) Valente, C.; Pedro,
M.; Ascenso, J. R.; Abreu, P. M.; Nascimento, M. S. J.; Ferreira, M.-J. U.
Planta Med. 2004, 70, 244-249.
‡ New address: Universita¨t Dortmund, Fachbereich 3, Organische
Chemie, Otto-Hahn-Straâe 6, D-44221 Dortmund, Germany.
(1) (a) Singla, A. K.; Pathak, K. Fitoterapia 1990, 61, 483-516. (b)
Evans, F. J.; Taylor, S. E. Fortschr. Chem. Org. Naturst. 1983, 44, 1-99.
(2) The first diterpene featuring the jatrophane skeleton was isolated from
Jatropha gossypiifolia; see: (a) Kupchan, S. M.; Sigel, C. W.; Matz, M.
J.; Renauld, J. A. S.; Haltiwanger, R. C.; Bryan, R. F. J. Am. Chem. Soc.
1970, 92, 4476-4477. (b) Kupchan, S. M.; Sigel, C. W.; Matz, M. J.;
Gilmore, C. J.; Bryan, R. F. J. Am. Chem. Soc. 1976, 98, 2295-2300. (c)
Taylor, M. D.; Smith, A. B.; Furst, G. T.; Gunasekara, S. P.; Bevelle, C.
A.; Cordell, G. A.; Farnsworth, N. R.; Kupchan, S. M.; Uchida, H.;
Branfman, A. R.; Dailey, R. G.; Sneden, A. T. J. Am. Chem. Soc. 1983,
105, 3177-3183.
(4) To the best of our knowledge, 17-norjatrophanes have not yet been
isolated as natural products.
(5) Hohmann, J.; Molnar, J.; Redei, D.; Evanics, F.; Forgo, P.; Kalman,
A.; Argay, G.; Szabo, P. J. Med. Chem. 2002, 45, 2425-2431.
(6) Borst, P.; Elferink, R. O. Annu. ReV. Biochem. 2002, 71, 537-592.
10.1021/ol060115t CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/16/2006

Several recent studies have investigated the structure-activity
relationship of jatrophanes as modulators of multidrug
resistance.8 However, these studies are so far restricted to
naturally occurring jatrophanes. Therefore, we have initiated
a research program aimed at the enantioselective de novo
synthesis of the jatrophane framework.9 We envision provid-
ing access to purposeful functionalized nonnatural jatro-
phanes for systematic structure-activity studies.
Scheme 1. Retrosynthetic Analysis of 2a
At the outset, we selected 15-acetyl-3-propionyl-characiol
2a for the initial development of a reliable synthetic strategy
toward the jatrophane framework (Figure 1). Originally, Seip
Figure 1. Jatrophane framework (1), 15-acetyl-3-propionyl-chara-
ciol (2a), and the 17-nor derivative (2b). The depicted numbering
is used throughout the paper.
The synthesis of the R-keto ester 7 began with an
asymmetric aldol addition utilizing the N-acylated Evans
auxiliary 8 (Scheme 2).11 The removal12 of the auxiliary
and Hecker reported the isolation of 2a from the latex of
Euphorbia characias.10 The gross structure and the relative
configuration of 2a were deduced from NMR studies.
Our initial retrosynthetic analysis of 15-acetyl-3-pro-
pionyl-characiol (2a) utilized a ring-closing metathesis
(RCM) transform to disconnect the stereogenic trisubstituted
C5/C6 double bond providing the synthon 3a (Scheme 1).
Disconnection of the C12/C13 double bond of 3a afforded
the â-keto phosphonate 4 and the aldehyde 5a. The â-keto
phosphonate 4 was further simplified to the highly substi-
tuted cyclopentane building block 6. Having identified a
carbonyl ene retron in 6, we opted for the disconnection of
the C4/C5 bond by a carbonyl ene transform to provide the
R-keto ester 7. Thus, pivotal steps of the retrosynthesis are
a RCM to close a 12-membered carbacycle by the formation
of a trisubstituted double bond and a diastereoselective
intramolecular carbonyl ene reaction for the synthesis of the
highly substituted cyclopentane fragment 6.
Scheme 2. Synthesis of the R-Keto Ester 7
(7) Robert, J.; Jarry, C. J. Med. Chem. 2003, 46, 4805-4817.
(8) (a) Corea, G.; Fattorusso, E.; Lanzotti, V.; Taglialatela-Scafati, O.;
Appendino, G.; Ballero, M.; Simon, P.-N.; Dumontet, C.; Di Pietro, A. J.
Med. Chem. 2003, 46, 3395-3402. (b) Valente, C.; Ferreira, M. J. U.;
Abreu, P. M.; Gyemant, N.; Ugocsai, K.; Hohmann, J.; Molnar, J. Planta
Med. 2004, 70, 81-84. (c) Corea, G.; Fattorusso, E.; Lanzotti, V.; Motti,
R.; Simon, P.-N.; Dumontet, C.; Di Pietro, A. J. Med. Chem. 2004, 47,
988-992. (d) Corea, G.; Fattorusso, E.; Lanzotti, V.; Motti, R.; Simon,
P.-N.; Dumontet, C.; Pietroio, A. D. Planta Med. 2004, 70, 657-665.
(9) For a preliminary communication, see: Helmboldt, H.; Rehbein, J.;
Hiersemann, M. Tetrahedron Lett. 2004, 45, 289-292. For other synthetic
approaches toward jatrophane diterpenes from Euphorbia, see: (a) Gilbert,
M. W.; Galkina, A.; Mulzer, J. Synlett 2004, 2558-2562. (b) Mulzer, J.;
Giester, G.; Gilbert, M. HelV. Chim. Acta 2005, 88, 1560-1579. For the
total synthesis of jatrophone, a jatrophane diterpene from Jatropha
gossypiifolia, see: (c) Smith, A. B.; Lupo, A. T.; Ohba, M.; Chen, K. J.
Am. Chem. Soc. 1989, 111, 6648-6656. (d) Gyorkos, A. C.; Stille, J. K.;
Hegedus, L. S. J. Am. Chem. Soc. 1990, 112, 8465-8472. (e) Han, Q.;
Wiemer, D. F. J. Am. Chem. Soc. 1992, 114, 7692-7697.
provided the â-hydroxy ester 9 that was protected, reduced
to the primary alcohol, and subsequently oxidized13 to afford
(10) Seip, E. H.; Hecker, E. Phytochemistry 1984, 23, 1689-1694.
(11) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127-2129.
(12) See ref 11. However, addition of NaOMe at -78 °C was mandatory
for optimal yields. The auxiliary was recovered in 97% yield under these
conditions.
1574
Org. Lett., Vol. 8, No. 8, 2006

the aldehyde 10 as a single diastereomer. To convert the
aldehyde to the desired R-keto ester 7, a two-step sequence
was established consisting of a Horner-Wadsworth-Em-
mons olefination utilizing the phosphonate 1114 and a
subsequent transesterification to provide the R-keto ester 7.15
The pivotal thermal intramolecular carbonyl ene reaction
was studied next (Scheme 3). Heating the R-keto ester 7 in
Scheme 4. Synthesis of the Substrates for the RCM
Scheme 3. Thermal Intramolecular Carbonyl Ene Reaction
a sealed tube for several days to 185 °C afforded a mixture
of the two diastereomeric cyclopentanes 6 and 13 which were
separable by flash chromatography.16 The relative configu-
ration of 6 and 13 was deduced from NOESY studies and
later confirmed for 6 by an X-ray crystal structure analysis
of a derivative.17
Under the thermal reaction conditions, the stereochemical
outcome of the ene reaction is thermodynamically controlled.
Subjecting pure 6 or 13 to the identical thermal conditions
afforded the same ratio of diastereomers as that originally
observed from 7. Therefore, recycling of the undesired
diastereomer 13 is possible and increases the overall ef-
ficiency of the ene reaction. Thus, the cyclopentane building
block 6 is conveniently accessible in an eight-step scalable
sequence with an overall yield of 34%. To obtain the required
absolute configuration at C4 and C15 from the ene reaction,
it was mandatory to utilize the R-keto ester 7 that features
the nonnatural absolute configuration at C3.
The synthesis was continued by protecting the tertiary
hydroxyl group of 6 as a trimethylsilyl (TMS) ether that
was sufficiently stable for the ensuing transformations
(Scheme 4).
A Claisen-type condensation with diethyl ethylphospho-
nate provided the â-keto ester 4 which was subsequently
deprotonated and treated with the aldehyde 5a18 to afford
the R,â-unsaturated ketone 14a as a single double-bond
isomer. Our original plan was to perform the RCM as late
as possible in the synthesis. Therefore, the TMS and the
triethylsilyl (TES) protecting group were removed and the
secondary hydroxyl group at C9 was oxidized employing
the Dess-Martin periodinane.19 The tert-butyldimethylsilyl
(TBS) ether was then cleaved to afford the diol 15a featuring
the undesired absolute configuration at C3. As expected, the
configuration at C3 could be inverted by a Mitsunobu
reaction20 to provide the corresponding benzoate which was
transesterificated to afford the C3 alcohol. Finally, regiose-
lective acylation of the secondary hydroxyl group in the
presence of 1-[3-(dimethylamino)propyl]-3-ethyl-carbodi-
imide hydrochloride21 (EDC) afforded the ester 3a.
With the triene 3a in hand, we attempted the crucial
RCM22 to establish the 12-membered carbacycle.23 However,
the employment of the first24 or second generation25 Grubbs
catalyst or the Hoveyda catalyst26 for this purpose was
(19) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(20) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,
2380-2382. (b) Mitsunobu, O. Synthesis 1981, 1-28.
(21) Sheehan, J.; Cruickshank, P.; Boshart, G. J. Org. Chem. 1961, 26,
2525-2528.
(22) For selected recent reviews, see: (a) Nicolaou, K. C.; Bulger, P.
G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490-4527. (b) Grubbs,
R. H. Tetrahedron 2004, 60, 7117-7140. (c) Deiters, A.; Martin, S. F.
Chem. ReV. 2004, 104, 2199-2238.
(13) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505-
5507.
(14) Schmidt, U.; Langner, J.; Kirschbaum, B.; Brau, C. Synthesis 1994,
1138-1140. However, a modified procedure for the preparation of 11 was
utilized. See the Supporting Information for details.
(15) We thank Dr. Michael Harre, Schering AG Berlin, for bringing the
phosphonate 11 to our attention and for providing a procedure for its large-
scale preparation and application.
(16) Microwave irradiation and the application of ionic liquids are
currently under investigation. Lewis acid based protocols have been reported
for the intramolecular carbonyl ene reaction of R-keto esters; see: (a) Kaden,
S.; Hiersemann, M. Synlett 2002, 1999-2002. (b) Yang, D.; Yang, M.;
Zhu, N. Org. Lett. 2003, 5, 3749-3752. However, attempts to utilize these
protocols were unsuccessful. Initial attempts to employ the anti-(3S,4R)-
configured R-keto ester 7 as the substrate for the ene reaction failed.
However, further studies are ongoing and the results will be reported as
part of a full paper.
(23) For recent reports on the synthesis of medium rings and macrocycles
via the formation of a trisubstituted double bond by RCM, see: (a)
Crimmins, M. T.; Ellis, J. M. J. Am. Chem. Soc. 2005, 127, 17200-17201
(9-membered). (b) Nicolaou, K. C.; Montagnon, T.; Vassilikogiannakis, G.;
Mathison, C. J. N. J. Am. Chem. Soc. 2005, 127, 8872-8888 (11-
membered). (c) Smith, A. B.; Mesaros, E. F.; Meyer, E. A. J. Am. Chem.
Soc. 2005, 127, 6948-6949 (16-membered).
(24) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
118, 100-110.
(25) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(17) See the Supporting Information for details.
(18) See the Supporting Information for details of the synthesis of 5a,b.
(26) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168-8179.
Org. Lett., Vol. 8, No. 8, 2006
1575

unsuccessful. Mainly starting material along with varying
amounts of inseparable and unidentified byproducts could
be isolated. The same result was obtained when other
partially or fully protected intermediates of the synthetic
sequence that had afforded 3a were subjected to the RCM
conditions.27 Consequently, we reasoned that the steric
requirements for the formation of the trisubstituted C5/C6
double bond are responsible for the failure of the RCM. A
successful RCM of a substrate that lacks the C17 methyl
group would validate this assumption. Therefore, the ester
3b was synthesized from 4 via 14b and 15b utilizing the
aldehyde 5b (Scheme 4). Gratifyingly, the subsequent RCM
of 3b proceeded successfully using the second generation
Grubbs catalyst (16) to provide the 17-norjatrophane 17 as
a single E-configured28 double-bond isomer (Scheme 5).
Finally, the acetylation of the tertiary hydroxyl group with
acetic anhydride in the presence of catalytic amounts of
TMSOTf provided 15-acetyl-3-propionyl-17-norcharaciol
(2b).29
In summary, attempts to generate the 12-membered
carbacycle of 15-acetyl-3-propionyl-characiol (2a) by the
formation of the trisubstituted C5/C6 double bond by RCM
were futile. However, RCM of 3b under formation of a
disubstituted C5/C6 double bond was successful and provided
access to the corresponding 17-norjatrophane 2b. The
enantioselective synthesis of 2b was accomplished in a highly
convergent manner, requiring a longest linear sequence of
20 steps with an overall yield of 3.5%. Modified strategies
for the synthesis of jatrophane diterpenes that circumvent
the encountered problem are currently under investigation
in our laboratory.
Acknowledgment. Very generous financial support from
the DFG and the FCI is gratefully acknowledged. We thank
Prof. Bernd Schmidt for helpful discussions and advice
related to ring-closing metathesis and Pia Schwab for an
X-ray crystallographic analysis.
Supporting Information Available: Experimental pro-
cedures and copies of NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 5. RCM of 3b and Final Acetylation
OL060115T
(27) The relay ring-closing metathesis (RRCM, see: Hoye, T. R.; Jeffrey,
C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc. 2004,
126, 10210-10211) utilizing a structurally modified substrate did not afford
the desired trisubstituted double bond. Details will be published as part of
a full paper.
(28) Assignment based on NOESY and ROESY studies. See the
Supporting Information for details.
(29) Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G. G. A. J.
Org. Chem. 1998, 63, 2342-2347.
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