General synthesis of highly functionalized cyclopentane segments for the preparation of jatrophane diterpenes

Article abstract of DOI:10.1021/ol902221y

Short and efficient syntheses of two diastereomeric cyclopentane segments present in most jatrophane diterpenes were achieved. Key steps are a stereoselective C-2 elongation, an RCM, and a hydroboration reaction. An orthogonal protecting group methodology

Full text of DOI:10.1021/ol902221y

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5326-5328
General Synthesis of Highly
Functionalized Cyclopentane Segments for
the Preparation of Jatrophane Diterpenes†
Christoph Lentsch and Uwe Rinner*
Institute of Organic Chemistry, UniVersity of Vienna, Wa¨hringerstrasse 38,
A-1090 Vienna, Austria
uwe.rinner@uniVie.ac.at
Received October 5, 2009
ABSTRACT
Short and efficient syntheses of two diastereomeric cyclopentane segments present in most jatrophane diterpenes were achieved. Key steps
are a stereoselective C-2 elongation, an RCM, and a hydroboration reaction. An orthogonal protecting group methodology makes these segments
useful building blocks for diterpene synthesis.
Since the isolation of jathrophone in 1970 by Kupchan,1 the
interest in active ingredients in members of the Euphorbi-
aceae family is steadily increasing. The milky latices of
Euphorbia species contain a vast number of structurally
diverse diterpenes, and a considerable amount of terpenes
from the tigliane, ingenane, daphnane, and jatrophane
families were isolated.2 Among the protruding biological
activities of many of these natural products, antiproliferative
activity3 and multidrug resistance modulating properties4,5
are most remarkable.
and selected examples of biologically interesting members
of this class of natural products are shown in Figure 1.
Despite the large number of jatrophane diterpenes isolated,
the interesting synthetic challenge, and the promising
biological properties, preparative work on this class of natural
products can be regarded as a new field as only a few
research groups are actively pursuing the synthesis of
Euphorbiaceae constitutents.6-8
A common strucutral motif of the cyclopentane moiety
of jatrophane diterpenes is the methyl group at C2 (jatrophane
numbering) which can be present in either an R or S
configuration as well as an oxygen functionality at C3 (Figure
1). The stereochemical pattern of this oxygen at C3 is
identical in all jatrophane diterpenes with a small number
The general structure of the jatrophane skeleton, a highly
functionalized trans-bicyclo[10.3.0]pentadecane framework,
† Dedicated to Prof. Tomas Hudlicky on the occasion of his 60th birthday
in recognition of his contributions to synthetic organic chemistry.
(1) 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.
(2) Shi, Q. W.; Su, X. H.; Kiyota, H. Chem. ReV. 2008, 108, 4295.
(3) Valente, C.; Pedro, M.; Duarte, A.; Nascimento, M. S. J.; Abreu,
P. M.; Ferreira, M. J. U. J. Nat. Prod. 2004, 67, 902.
(4) Hohmann, J.; Evanics, F.; Dombi, G.; Molnar, J.; Szabo, P.
Tetrahedron 2001, 57, 211.
(5) Valente, C.; Ferreira, M. J. U.; Abreu, P. M.; Gyemant, N.; Ugocsai,
K.; Hohmann, J.; Molnar, J. Planta Med. 2004, 70, 81.
10.1021/ol902221y CCC: $40.75
Published on Web 10/26/2009
 2009 American Chemical Society

reaction was envisaged to be prepared by oxidation of
alcohols 7a and 7b, both readily available, and stereoselective
C2 elongation of the corresponding aldehydes, followed by
Eschenmoser methylenation.11
Scheme 1. Retrosynthetic Analysis
Figure 1. Jatrophane skeleton and selected diterpenes.
of exceptions. Although cylopentanes are common structural
motifs in natural products, the syntheses of such segments
are often lengthy and tedious, especially when highly
functionalized.
While designing a synthesis of Pl-3 (1), a biologically
highly active member of the jatrophane family which was
first isolated by Hohmann in 2003 from Euphorbia platy-
phyllos,9 we envisaged to devise a short and more general
approach toward the five-membered ring segment to get
access to various diterpenes of this family of natural products
such as altotibetin A (2)10 with reversed stereochemistry of
the methyl group at C2. Synthetic equivalents required for
preparing the corresponding natural products are shown in
Figure 2.
Alcohols 7a and 7b were prepared by Myers’ alkylation
of the corresponding pseudoephedrine propionamide with
allyl iodide and LAB reduction following a literature
procedure.12 Oxidation of alcohol 7 with IBX under standard
conditions cleanly afforded aldehyde 8. The high volatility
of this material complicated the workup; however, direct
distillation of the aldehyde from the reaction mixture afforded
the product in good yield. The stereochemical stability of
this R-chiral aldehyde, even after prolonged storage at room
temperature, was demonstrated by reduction of the carbonyl
group and subsequent conversion to the corresponding
Mosher ester. Stereoselective C2-elongation was achieved
in excellent yield using (R)-HYTRA (9) as chiral auxiliary.13
As the determination of the diastereomeric ratio was not
possible at this point, compound 10 was further transesterified
to the corresponding methyl ester in quantitative yield using
sodium methoxide. Interpretation of NMR spectra revealed
a diastereomeric ratio of at least 10:1 for both esters 6a and
6b.
A crucial step in the reaction sequence was the
incorporation of the exomethylene functionality. Origi-
nally, we intended to apply Eschenmoser’s salt,11 but all
attempts resulted in either reisolation of the starting
material when alcohol 6 was used or elimination if the
Figure 2. Natural product motif and synthetic equivalent.
The retrosynthetic analysis for the preparation of ketones
4a and 4b is outlined in Scheme 1. The key step in this
sequence is a RCM reaction to establish the five-membered
ring from linear precursors.
The double bond generated in this reaction can be used in
a directed hydroboration/oxidation protocol to install the
ketone functionality and to define the stereochemistry of the
latter ring junction at C4. The precursor for the key RCM
(8) (a) Helmboldt, H.; Rehbein, J.; Hiersemann, M. Tetrahedron Lett.
2004, 45, 289. (b) Helmboldt, H.; Ko¨hler, D.; Hiersemann, M. Org. Lett.
2006, 8, 1573. (c) Helmboldt, H.; Hiersemann, M. J. Org. Chem. 2009, 74,
1698. (d) Schnabel, C.; Hiersemann, M. Org. Lett. 2009, 11, 2555.
(9) Hohmann, J.; Forgo, P.; Csupor, D.; Schlosser, G. HelV. Chim. Acta
2003, 86, 3386.
(10) (a) Hohmann, J.; Redei, D.; Forgo, P.; Molnar, J.; Dombi, G.; Zorig,
T. J. Nat. Prod. 2003, 66, 976. (b) Pan, L.; Zhang, X. F.; Deng, Y.; Wang,
H.; Wu, D. G.; Luo, X. D. HelV. Chim. Acta 2003, 86, 2525.
(11) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. Ed. Engl. 1971, 10, 330.
(6) (a) Gilbert, M.; Galkina, A.; Mulzer, J. Synlett 2005, 2558. (b)
Mulzer, J.; Giester, G.; Gilbert, M. HelV. Chim. Acta 2005, 88, 1560.
(7) Shimokawa, K.; Takamura, H.; Uemura, D. Tetrahedron Lett. 2007,
48, 5623.
(12) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496.
(13) (a) Braun, M.; Graf, S. Org. Synth. 1995, 72, 38. (b) Braun, M.;
Graf, S.; Herzog, S. Org. Synth. 1995, 72, 32.
Org. Lett., Vol. 11, No. 22, 2009
5327

hydroxyl group was protected as the silyl ether prior to
the reaction. The problem could be solved by treatment
of double-deprotonated ester 6 with freshly prepared
formaldehyde solution, conversion of the primary hydroxy
functionality into the corresponding tosylate, and elimina-
tion effected by exposure of this material to DBU.14
Protection of the secondary alcohol as silyl ether afforded
12 in good yield (Scheme 2). The ester functionality in
Scheme 3. Synthesis of Cyclopentanes 4a and 4b
Scheme 2. Preparation of Ester 12
The synthesis of highly versatile cyclopentane fragments
4a and 4b present in most jatrophane diterpenes has been
12 was further reduced using DIBAL-H at 0 °C and
converted to PMB-ether 13 using Bundle’s reagent.15 This
material served as precursor for the key RCM reaction.
Exposure of this material to Grubbs’ second-generation
catalyst16 cleanly afforded cyclopentene derivative 14
which was used in the hydroboration reaction with
thexylborane.17 The bulkiness of the silyl ether prevented
attack of the borane reagent from the top face of the
molecule and selectively affords the desired stereoisomer
(15). Oxidation of the hydroxyl functionality concludes
the synthetic route and delivers ketones 4a and 4b in
excellent yield (Scheme 3).
Figure 3. NOE correlations in cyclopentanes 15a and 15b.
achieved in only 12 steps and good overall yield. Further
application of these highly functional five membered ring
segments in the preparation of jatrophane diterpenes is
currently under investigation and will be reported in due
course.
Acknowledgment. We thank Dr. Hanspeter Ka¨hlig (Uni-
versity of Vienna) for assistance with NMR spectra. The
Fonds zur Fo¨rderung der wissenschaftlichen Forschung
(FWF) is gratefully acknowledged for financial support of
this work (Project Nos. FWF-R45-N19 and FWF-P20697-
N19).
The stereochemical relationship of the substituents on the
cyclopentyl ring was unambiguously elucidated and proven
by NOE correlation experiments. The crucial cross-couplings
are illustrated in Figure 3.
Supporting Information Available: Experimental pro-
cedures for all new compounds and selected NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Phukan, P.; Bauer, M.; Maier, M. E. Synthesis 2003, 1324.
(15) Iversen, T.; Bundle, D. R. J. Chem. Soc., Chem. Commun. 1981,
1240.
(16) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
(17) Castagner, B.; Leighton, J. L. Tetrahedron 2007, 63, 5895.
OL902221Y
5328
Org. Lett., Vol. 11, No. 22, 2009