Synthetic studies toward jatrophane diterpenes from Euphorbia characias. enantioselective synthesis of (-)-15-O-Acetyl-3-O-propionyl-17-norcharaciol

Article abstract of DOI:10.1021/jo802581g

The enantioselective synthesis of (+)-17-norcharaciol is described. An uncatalyzed intramolecular carbonyl-ene reaction and a ring-closing metathesis were used as key C/C-connecting transformations to assemble the trans-bicyclo[10.3.0]pentadecane norditerpenoid core. We also report the evolution of our synthetic strategy toward the fully substituted characiol skeleton and the experiences from this venture.

Full text of DOI:10.1021/jo802581g

Synthetic Studies toward Jatrophane Diterpenes from Euphorbia
characias. Enantioselective Synthesis of
(-)-15-O-Acetyl-3-O-propionyl-17-norcharaciol†
Hannes Helmboldt‡ and Martin Hiersemann*
Fakulta¨t Chemie, Technische UniVersita¨t Dortmund, Dortmund 44227, Germany
martin.hiersemann@udo.edu
ReceiVed NoVember 20, 2008
The enantioselective synthesis of (+)-17-norcharaciol is described. An uncatalyzed intramolecular
carbonyl-ene reaction and a ring-closing metathesis were used as key C/C-connecting transformations
to assemble the trans-bicyclo[10.3.0]pentadecane norditerpenoid core. We also report the evolution of
our synthetic strategy toward the fully substituted characiol skeleton and the experiences from this venture.
Introduction
Euphorbia (Euphorbiaceae, spurge family) represents a genus
of about 2000 species.1 The majority of these Euphorbia species
are herbaceous with a worldwide distribution in temperate and
tropical zones.2 Tree, shrubby, and succulent Euphorbia species
are found almost exclusively in the tropics and subtropics. An
often caustic milky latex is abundant in all parts of the plants.
Euphorbia species are a prolific source for polycyclic diterpe-
nes.3 The plants have found widespread application in traditional
folk medicine as well as gained the attention of the pharma-
ceutical industry.4
FIGURE 1. Jatrophane basic framework (1) and jatrophone (2) from
Jatropha gossypiifolia.
member within this diverse diterpene family, from the roots of
Jatropha gossypiifolia.5,6
Euphoria characias, an evergreen perennial with a bushy
habit, is widely distributed in the Mediterranean region. In 1984,
Seip and Hecker reported the isolation and structural elucidation
of eight jatrophane diterpenes (3b-i) from the latex and roots
Jatrophanes, the dominant bicylic diterpenes from Euphorbia
sp., are characterized by a bicyclo[10.3.0]pentadecane core (1,
Figure 1). In 1970, Kupchan and co-workers reported the
isolation and structural elucidation of jatrophone (2), the first
(5) (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) Purushothaman, K. K.; Chandrasekharan,
S.; Cameron, A. F.; Connolly, J. D.; Labbe´, C.; Maltz, A.; Rycroft, D. S.
Tetrahedron Lett. 1979, 20, 979–980. (d) 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.
(6) For completed total syntheses of jatrophone, see: (a) Smith, A. B.;
Guaciaro, M. A.; Schow, S. R.; Wovkulich, P. M.; Toder, B. H.; Hall, T. W.
J. Am. Chem. Soc. 1981, 103, 219–222. (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.
† Dedicated to the memory of Prof. Wolfgang Kreiser.
‡ Present adress: Labor fu¨r Prozessforschung, Organisch Chemisches Institut,
Universita¨t Zu¨rich-Irchel, Switzerland.
(1) Sitte, P.; Weiler, E. W.; Kadereit, J. W.; Bresinsky, A.; Ko¨rner, C.
Strasburger - Lehrbuch der Botanik, 35th ed.; Spektrum Akad. Verl.: Heidelberg,
2002; pp 826-828.
(2) Carter, S. In Dicotyledons; Eggli, U., Ed.; Springer: Berlin, 2004; pp
102-203.
(3) (a) Evans, F. J.; Taylor, S. E. Fortschr. Chem. Org. Naturst. 1983, 44,
1–99. (b) Singla, A. K.; Pathak, K. Fitoterapia 1990, 61, 483–516.
(4) Davis, C.; Parsons, P. Report for the Rural Industries Research and
Development Corporation (RIRDC), Publication No. 02/001, 2002, pp 1-10.
1698 J. Org. Chem. 2009, 74, 1698–1708
10.1021/jo802581g CCC: $40.75 2009 American Chemical Society
Published on Web 01/13/2009

Synthetic Studies toward Jatrophane Diterpenes
FIGURE 3. ∆5,6 12,13-Jatrophanes containing an all-cis-configured
∆
cyclopentane fragment.
multidrug resistance modulating activity,17 and inhibition of the
P-glycoprotein.18 These findings coupled with intriguing struc-
ture of the densely functionalized bicyclic jatrophane core have
prompted synthetic efforts by the groups of Mulzer19 and
Uemura,20 as well as our group.21
In this paper, we report in detail the results from a research
program that is aimed at the total synthesis of jatrophane
diterpenes that are characterized by a C5/C6 and C12/13 double
bond as well as an all-cis-configured cyclopentane segment. The
diester 3b is the structurally most simple jatrophane within this
diterpene family (Figure 3). The structurally related jatrophanes
3l-n have been isolated from Euphorbia pubescens (Figure 3).22
A moderate cell type selective growth inhibitory effect on the
nonsmall cell lung cancer cell line (NCI-H460) has been
reported for 3l-n.
FIGURE 2. Jatrophane diterpenes from E. characias.
of E. characias (Figure 2).7 Essentially, they assigned the
relative and absolute configuration of the jatrophanes 3b-i by
analogy to related lathyrane diterpenes for which the structure
had been unambiguously assigned by X-ray single crystal
diffraction.8 The positioning of the acyl groups was based on
NMR data, transesterification experiments, or simply, by anal-
ogy. For the jatrophanes 3h,i, the exact positioning of the acyl
substituents and the configuration of the stereogenic carbon
atoms C8 and C13 was not rigorously verified. Hence, the
unambiguous assignment of the gross structure and configuration
of these jatrophanes awaits further investigations. Twenty years
after the study of Seip and Hecker, Lanzotti and co-workers
reported the isolation of 12 jatrophane diterpenes, named
euphocharacins A-L (EA-L), from E. characias.9 It was found
that the euphocharacins 3j and 3k (Figure 2) are stronger
inhibitors of the cellular P-glycoprotein-mediated daunomycin
efflux than cyclosporine A, a compound which was advanced
to clinical trials as a multidrug-resistance reversal agent.10
A variety of different biological activities have been reported
for jatrophane diterpenes: inhibitory activity on the mammalian
mitochondrial respiratory chain,11 cell cleavage arrest,12 cyto-
toxicity against various human cancer cell lines,13 antiviral
activity,14 antiplasmodial activity,15 microtubule interaction,16
Results and Discussion
Synthesis of the Cyclopentane Building Block. Our original
initiative focused on the development of a synthetic access to
characiol (3a) as a relay compound for a subsequent synthesis
of the jatrophanes 3b-d (Figure 4).
In the synthesis of the bicyclic jatrophane core, the major
obstacle was anticipated to be the trans-anulation of the 12-
membered ring, containing 6 sp2-hybrized carbon atoms in the
relatively short tether, onto the highly substituted 5-membered
ring. Nevertheless, we opted for a retrosynthesis that disconnects
the C13/C14 bond and provides the vinyl anion synthon 4, which
should be accessible from a vinyl iodide under appropriate
halogen-metal exchange conditions (Figure 4). This discon-
nection mode was selected on the basis of the ample literature
evidence for the utility of the Nozaki-Hiyama-Kishi (NHK)
(7) Seip, E. H.; Hecker, E. Phytochemistry 1984, 23, 1689–1694. The parent
diol 3a, named characiol by Seip and Hecker, has not been isolated from the
natural source.
(8) (a) Narayanan, P.; Ro¨hrl, M.; Zechmeister, K.; Engel, D. W.; Hoppe,
W.; Hecker, E.; Adolf, W. Tetrahedron Lett. 1971, 12, 1325–1328. (b) Seip,
E. H.; Hecker, E. Phytochemistry 1983, 22, 1791–1795.
(9) Corea, G.; Fattorusso, E.; Lanzotti, V.; Motti, R.; Simon, P.-N.; Dumontet,
C.; Pietroio, A. D. Planta Med. 2004, 70, 657–665.
(10) Robert, J.; Jarry, C. J. Med. Chem. 2003, 46, 4805–4817.
(11) Betancur-Galvis, L.; Checa, J.; Marco, J. A.; Estornell, E. Planta Med.
2003, 69, 177–178.
(12) Wang, L.-Y.; Wang, N.-L.; Yao, X.-S.; Miyata, S.; Kitanaka, S. J. Nat.
Prod. 2002, 65, 1246–1251.
(13) Valente, C.; Pedro, M.; Ascenso, J. R.; Abreu, P. M.; Nascimento,
M. S. J.; Ferreira, M.-J. U. Planta Med. 2004, 70, 244–249.
(14) Mucsi, I.; Molna´r, J.; Hohmann, J.; Re´dei, D. Planta Med. 2001, 67,
672–674.
(15) Adelekan, A. M.; Prozesky, E. A.; Hussein, A. A.; Urena, L. D.; van
Rooyen, P. H.; Liles, D. C.; Meyer, J. J. M.; Rodriguez, B. J. Nat. Prod. 2008,
71, 1919–1922.
(16) Buey, R. M.; Barasoain, I.; Jackson, E.; Meyer, A.; Giannakakou, P.;
Paterson, I.; Mooberry, S.; Andreu, J. M.; Diaz, J. F. Chem. Biol. 2005, 12,
1269–1279.
(17) (a) Barile, E.; Borriello, M.; Pietro, A. D.; Doreau, A.; Fattorusso, C.;
Fattorusso, E.; Lanzotti, V. Org. Biomol. Chem. 2008, 6, 1756–1762. (b) Corea,
G.; Fattorusso, E.; Lanzotti, V.; Motti, R.; Simon, P.-N.; Dumontet, C.; Di Pietro,
A. J. Med. Chem. 2004, 47, 988–992.
(18) (a) Corea, G.; Fattorusso, E.; Lanzotti, V.; Motti, R.; Simon, P.-N.;
Dumontet, C.; Pietroio, A. D. Planta Med. 2004, 70, 657–665. (b) 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.
(19) (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.
(20) Uemura, T.; Suzuki, T.; Onodera, N.; Hagiwara, H.; Hoshi, T.
Tetrahedron Lett. 2007, 48, 715–719.
(21) (a) Helmboldt, H.; Rehbein, J.; Hiersemann, M. Tetrahedron Lett. 2004,
45, 289–292. (b) Helmboldt, H.; Ko¨hler, D.; Hiersemann, M. Org. Lett. 2006,
8, 1573–1576.
(22) (a) Valente, C.; Ferreira, M. J. U.; Abreu, P. M.; Gyemant, N.; Ugocsai,
K.; Hohmann, J.; Molnar, J. Planta Med. 2004, 70, 81–84. (b) Valente, C.;
Ferreira, M. J. U.; Abreu, P. M.; Pedro, M.; Cerqueira, F.; Nascimento, M. S. J.
Planta Med. 2003, 69, 361–366.
J. Org. Chem. Vol. 74, No. 4, 2009 1699

Helmboldt and Hiersemann
SCHEME 1. Synthesis of the r-Keto Ester 6a
FIGURE 4. Initial retrosynthetic analysis.
FIGURE 5. Qualitative model for the expected stereochemical course
of the carbonyl-ene reaction (E ) CO2Me).
of the auxiliary,27 the ꢀ-hydroxy ester 8 which was protected,28
reduced to the alcohol, and subsequently oxidized29 to the
corresponding aldehyde 9.30 We then faced the requirement of
a two-carbon chain homologation with concomitant introduction
of the R-keto ester moiety. A two-step sequence was utilized
for this purpose. First, a Horner-Wadsworth-Emmons reac-
tion31 between the aldehyde 9 and methyl 2-(tert-butyldimeth-
ylsiloxy)-2-(dimethoxyphosphoryl)acetate (10a) according to
Nakamura afforded the stable silyl enol ether 11a as an E/Z )
10/1 mixture of double bond isomers.32 Chemoselective cleav-
age of the silyl enol ether in the presence of the silyl alkyl ether
with CsF provided the desired R-keto ester 6a in very good
overall yield.33,34 We then studied the utility of ethyl 2-acetoxy-
2-(diethyloxyphosphoryl)acetate (10b) as replacement for 10a.
Treatment of the aldehyde 9 with the phosphonoacetate 10b
and 1,1,3,3-tetramethylguanidine in the presence of LiCl35
provided the vinyl acetate 11b in slightly lower yield and
decreased E/Z diastereoselectivity compared to the application
of 10a. The inseparable (E/Z)-mixture of the vinyl acetates 11b
was subsequently treated with catalytic amounts of K2CO3 in
reaction for the synthesis of medium to large carbocycles.23
Further retrosynthetic simplification by the removal of the
C6-C13 chain leads to the highly substituted cyclopentanoid
5. Inspired by previous work on sequential pericyclic reactions,24
we have identified a carbonyl-ene reaction retron in 5 (ho-
moallylic alcohol segment in blue), and accordingly, the
cyclopentanoid 5 can be deconstructed to the acyclic R-keto
ester 6. We speculated that the absolute configuration of C3 in
the R-keto ester 6 in concert with the pericyclic nature of the
transition state of an uncatalyzed ene reaction would channel
the stereochemical course of the ene reaction in our favor (Figure
5). It was envisaged that the minimization of the 1,3-allylic
strain25 in the substrate conformer 6 and the corresponding
transition structure [6]q would cause a sufficient ∆∆Gq between
the two geometrically possible and competing transition states
[6]q and [6′]q. Our qualitative stereochemical model requires
an absolute configuration at C3 of the R-keto ester 6 that is
opposite to the absolute configuration of C3 in characiol (3a).
However, we were optimistic that an inversion of the config-
uration at C3 would be possible at an appropriate stage of the
synthesis.
(27) Addition of the sodium methoxide at-78 °C was essential to obtain
high yields.
(28) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190–
6191.
(29) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505–
5507.
(30) Bhatt, U.; Christmann, M.; Quitschalle, M.; Claus, E.; Kalesse, M. J.
Org. Chem. 2001, 66, 1885–1893.
We began with the development of a scalable and robust
enantioselective synthesis of the R-keto ester 6 (Scheme 1).
Evans aldol chemistry26 was utilized to provide, after removal
(31) (a) Horner, L.; Hoffmann, H.; Wippel, H. G.; Klahre, G. Chem. Ber.
1959, 92, 2499–2507. (b) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem.
Soc. 1961, 83, 1733–1738.
(32) (a) Nakamura, E. Tetrahedron Lett. 1981, 22, 663–666. (b) Horne, D.;
Gaudino, J.; Thompson, W. J. Tetrahedron Lett. 1984, 25, 3529–3532.
(33) (a) Overman, L. E.; Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Am.
Chem. Soc. 1997, 119, 7159–7160. (b) Be´langer, G.; Hong, F.; Overman, L. E.;
Rogers, B. N.; Tellew, J. E.; Trenkle, W. C. J. Org. Chem. 2002, 67, 7880–
7883.
(34) Application of TBAF in THF at-78 °C gave inferior results.
(35) (a) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186.
(b) Rathke, M. W.; Nowak, M. J. Org. Chem. 1985, 50, 2624–2626.
(23) For reviews, see: (a) Fu¨rstner, A. Chem. ReV. 1999, 99, 991–1046. (b)
Avalos, M.; Babiano, R.; Cintas, P.; Jime´nez, J. L.; Palacios, J. C. Chem. Soc.
ReV. 1999, 28, 169–177. For applications with relevance to the present endeavor,
see: (c) Wilson, M. S.; Woo, J. C. S.; Dake, G. R. J. Org. Chem. 2006, 71,
4237–4245. (d) Matsuura, T.; Yamamura, S.; Terada, Y. Tetrahedron Lett. 2000,
41, 2189–2192.
(24) (a) Hiersemann, M. Eur. J. Org. Chem. 2001, 483–491.
(25) (a) Johnson, F.; Malhotra, S. K. J. Am. Chem. Soc. 1965, 87, 5492–
5493. (b) Malhotra, S. K.; Johnson, F. J. Am. Chem. Soc. 1965, 87, 5493–5495.
(c) Johnson, F. Chem. ReV. 1968, 68, 375–413.
(26) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127–2129.
1700 J. Org. Chem. Vol. 74, No. 4, 2009

Synthetic Studies toward Jatrophane Diterpenes
SCHEME 2. Intramolecular Carbonyl Ene Reaction
SCHEME 3. Introduction of the C6-C13 Segment
MeOH36 to provide the desired R-keto ester 6a, as well as the
unconsumed (Z)-configured vinyl acetate 11b as a mixture of
the corresponding methyl and ethyl esters.37 Attempts to force
the transesterification of (Z)-11b under various conditions were
unsuccessful. Nevertheless, due to its convenient preparation,
application and lower cost, the phosphonoacetate 10b is a viable
alternative to the higher yielding but more expensive phospho-
noacetate 10a. The sequence depicted in Scheme 1 has been
scaled to provide gram quantities of the R-keto ester 6a.
The pivotal carbonyl ene reaction was investigated in the
absence of potential catalysts to ensure the concertedness of
the mechanism (Scheme 2).38 Thus, a decane solution (25 mL)
of the R-keto ester 6a (1.5 g) in a glass pressure tube was heated
to 180-190 °C (bath temperature) for 3-5 days (TLC control)
and afforded the two diastereomeric cyclopentanoids 5a (63%)
and 12 (14%) which are separable by chromatography. Fur-
thermore, traces of the starting material 6a (5%) were detected
1
in the H NMR spectrum of the crude product mixture. The
relative configuration of the ene reaction products was initially
assigned by NOE spectroscopy and later verified by a X-ray
crystal structure analysis of a derivative of 5a.21b In accordance
with our original prediction, the major diastereomer 5a of the
ene reaction has the desired absolute configuration at C4 and
C15.
SCHEME 4. Inversion of the Absolute Configuration at C3
and Subsequent Attempts To Assemble the C5/C6 Double
Bond
In order to verify whether the product distribution of the ene
reaction is kinetically or thermodynamically controlled, the
separated diastereomeric ene reaction products 5a and 12 were
heated to 180 °C in decane and provided mixtures of 5a and
12 in roughly the same ratio (5a/12 ) 5/1) as obtained from
the original ene reaction of 6a. This outcome clearly indicates
that the product distribution of the ene reaction is thermody-
namically controlled. Hence, the otherwise useless minor
diastereomer 12 could be conveniently recycled to the building
block 5a. The thermodynamic preference for the major diaste-
reomer 5a can be attributed to a staggered arrangement of the
substituents at the four stereogenic carbon atoms (Figure 5).
The minor diastereomer 12 is destabilized by an eclipsed
arrangement of the substituent at C3 and C4.39
Attempted C12/C13 Ring Closure. The synthetic strategy
now required elaboration of the cyclopentanoid 5a to the alkyne
18 by chain elongation at C6 (Scheme 3). For this purpose, it
was required to reduce and protect the ester functionality at C14
first. Thus, treatment of the ester 6a with LiAlH4 was followed
by a Williamson ether synthesis to furnish the PMB40 ether 13.
At this juncture, we decided to pursue the inversion of the
absolute configuration of C3 (Scheme 4). The TBS protecting
group in 13 was removed to unmask the hydroxyl group at C3.
Mitsunobu reaction41 and subsequent protection of the remaining
free hydroxyl group as a TBS ether provided the benzoate 19
featuring the correct absolute configuration of all stereogenic
carbon atoms of the cyclopentane segment.42 Delighted by this
result, we attempted to introduce the C5/C6 double bond by
olefination. Ozonolysis of the double bond of the cyclopentanoid
19 afforded the aldehyde 20 which decomposed during the
attempted silica gel purification. The elimination product 23 was
isolated in low yield. The leaving group capacity of the benzoate
group along with its trans-diaxial arrangement to an acidified
proton is, for stereoelectronic reasons, supportive for this
(36) Attempts to use ethanol instead of methanol in combination with a variety
of different inorganic bases were unsuccessful.
(37) TLC control indicates that the transesterification of (E)-11b to the
corresponding methyl ester precedes the cleavage of the vinyl acetate moiety.
(38) 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.
(39) A computational study on the mechanistic details of the ene reaction
will be reported in a forthcoming article.
(41) (a) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380–
2382. (b) Mitsunobu, O. Synthesis 1981, 1–28. (c) Schenk, S.; Weston, J.; Anders,
E. J. Am. Chem. Soc. 2005, 127, 12566–12576.
(40) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron Lett.
1988, 29, 4139–4142.
(42) The relative configuration was assigned based on NOESY experiments.
See the Supporting Information for details.
J. Org. Chem. Vol. 74, No. 4, 2009 1701

Helmboldt and Hiersemann
SCHEME 5. Toward the Substrates for the Unsuccessful
Intramolecular NHK Reaction
undesired event. Consequently, it came to no surprise that the
attempted olefination of the sensitive aldehyde 20 with the
phosphonate 21 under conventional or Masamune-Roush
conditions43 led to a comparable result (Scheme 4).
In order to obviate the risk of the undesired elimination, we
decided to postpone the inversion of C3 to a later point of the
synthesis. Hence, we continued our synthetic efforts with
the cyclopentanoid 13 as depicted in Scheme 3. Protection of
the tertiary hydroxyl group as a TBS ether44 followed by
ozonolysis of the double bond afforded the aldehyde 14 which
could be purified by chromatography. Because more convergent
strategies failed (vide infra), we aimed for a stepwise construc-
tion of the C6 to C13 segment. Accordingly, olefination utilizing
a stabilized Wittig ylide45 and subsequent DIBAH reduction
furnished the E-configured allylic alcohol 15. Mesylation of the
primary hydroxyl group of 15 and subsequent Kolbe nitrile
synthesis provided the homologated cyanide. The cyano group
was then reduced with DIBAH46 via the aldehyde, and the
resulting homoallylic alcohol was converted into the homoallylic
iodide 16. The coupling of the iodide 16 with the aldehyde 17
was investigated next. Treatment of the homoallylic iodide 16
with tert-BuLi (2 equiv)47 and immediate addition of the
aldehyde 17 afforded the alcohol 18 as a 1/1 mixture of
diastereomers. Though initially quite successful, the coupling
reaction was unreliable and yields were fluctuating between
30-83%; the dominating byproduct was the corresponding
deiodinated substrate.48
We turned next to the elaboration of the alkyne 18 into the
(E)-configured vinyl iodide 26 needed for the pivotal ring-
closing nucleophilic addition (Scheme 5). For this purpose, the
C9 hydroxyl group of 18 was protected with two different silyl
protecting groups (TES, TIPS) to afford the alkynes 24a and
24b. The TIPS-protected alkyne 24a was then subjected to a
hydrozirconation/iodination protocol to provide 25a as a single
double-bond isomer.49 Subjecting the TES-protected alkyne 24b
to identical reaction conditions afforded the desired vinyl iodide
25b in inconsistent yields. The major byproduct was the alcohol
25c; the consequence of the cleavage of the TES protecting
group. Though the vinyl iodides 25b and 25c were isolated in
fluctuating amounts, the combined yield was constant and they
were separable by chromatography. The vinyl iodides 25a-c
were then treated with DDQ to remove the PMB-protecting
group50 and subsequently oxidized with TPAP/NMO51 (25b,c)
or DMSO/SO3 ·pyridine29 (25a) to afford the aldehydes 26a,b
as well as the keto aldehyde 27. With three structurally distinct
vinyl iodides available, the projected cyclization under
Nozaki-Hiyama-Kishi52 or iodine-lithium exchange47 condi-
tions was investigated next. Unfortunately, all efforts led only
to the decomposition or reisolation of the starting material.
Furthermore, the chemistry utilized for the preparation of the
cyclization precursors, which were needed further exploration
and optimization, was extremely cumbersome. With the inten-
tion of rendering the synthesis of the cyclization precursors more
convergent, two alternative approaches toward the alkyne 30
were investigated (Scheme 6).
Attempts to alkylate the enolate derived from the ketone 29a
or the hydrazone 29b53 under various conditions with the allylic
iodide 28 failed to provide the alkyne 30. In a second approach
to 30, we envisioned to utilize a Claisen rearrangement54 of
the allyl vinyl ether 31. However, in our hands, the allylic
alcohol 33 was reluctant to undergo an esterification with the
acid 32 under various esterification conditions.55
Attempted C5/C6 Ring Closure by RCM. Given the
difficulties encountered in the NHK cyclization attempts and
the overall length and the inefficiency of the synthetic sequence
toward the cyclization precursors, an alternate retrosynthesis of
characiol (3d) was required. Regarding convergence as key to
efficiency, we proposed a strategy that rested on the availability
of two larger fragments and the potential of the available
(43) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.; Masamune,
S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183–2186.
(44) Corey, E. J.; Cho, H.; Ru¨cker, C.; Hua, D. H. Tetrahedron Lett. 1981,
22, 3455–3458.
(45) Attempts to utilize the phosphonate 21 led to elimination.
(46) Miller, A. E. G.; Biss, J. W.; Schwartzman, L. H. J. Org. Chem. 1959,
24, 627–630.
(47) (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.
(48) Attempts to alkylate a lithiated 1,3-dithiane of the aldehyde 17 with the
homoallylic alcohol 16 also delivered the corresponding protodeiodinated
substrate.
(49) (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. For a review, see: (c) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853–
12910.
(50) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885–888. (b) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
O. Tetrahedron 1986, 42, 3021–3028.
(52) (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281–5284. (b) Jin, H.; Uenishi, J.; Christ, W. J.;
Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644–5646. (c) Takai, K.; Tagashira,
M.; Kuroda, T.; Oshima, K.; Utimoto, K.; Nozaki, H. J. Am. Chem. Soc. 1986,
108, 6048–6050. For the application of 4-tert-butylpyridine as an additive, see:
(d) Stamos, D. P.; Sheng, X. C.; Chen, S. S.; Kishi, Y. Tetrahedron Lett. 1997,
38, 6355–6358.
(53) For a successful application, see: Panek, J. S.; Jain, N. F. J. Org. Chem.
2001, 66, 2747–2756.
(54) The Claisen Rearrangement; Hiersemann, M., Nubbemeyer, U., Eds.;
Wiley-VCH:Weinheim, 2007.
(51) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639–666.
(55) (a) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827–
10852. (b) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447–2467.
1702 J. Org. Chem. Vol. 74, No. 4, 2009

Synthetic Studies toward Jatrophane Diterpenes
SCHEME 6. Unsuccessful Strategies for the Synthesis of the
Building Block 30
SCHEME 7. Synthesis of the Aldehydes 36a,b
synthetic methodology for double-bond formation. As depicted
in Figure 6, we envisioned to exploit a ring-closing metathesis56,57
(RCM) of the triene 34a to generate the C5/C6 double bond,
ideally in the absence of any protecting group. Disconnecting
the C12/C13 double bond of the R,ꢀ-unsaturated ketone 34a
by a HWE olefination31 transform leads to the synthons 35 and
36a. The required synthesis of the aldehyde 36a was no cause
of concern and the already developed ene reaction could be
utilized for the synthesis of the phosphonate 35.
SCHEME 8. Preparation of the Trienes 34a,b for the RCM
FIGURE 6. Second-generation retrosynthesis.
The synthesis of the aldehyde 36a commenced with the
protection of 2-iodoethanol (37) and was continued with the
alkylation of the lithium enolate of ethyl isobutyrate with TES-
protected 2-iodoethanol followed by a redox sequence to provide
the aldehyde 38 (Scheme 7). Exposure of the aldehyde 38 to a
Grignard reagent that was prepared from the highly volatile
4-iodo-2-methyl-1-butene furnished the alcohol 40a which was
protected as a TES ether. In situ removal of the TES protecting
group from the primary hydroxyl group and oxidation58 under
Swern59 conditions provided the desired aldehyde 36a.60
The synthesis of the phosphonate 41 from the major diaste-
reomer 5a of the ene reaction and the subsequent HWE
olefination with the aldehyde 36a was investigated next (Scheme
8). Following the protection of the tertiary hydroxyl group of
5a as trimethylsilyl ether, a Claisen-type condensation of the
(56) For selected recent examples for the formation of medium-sized rings
and macrocycles by RCM, see: (a) Toumi, M.; Couty, F.; Evano, G. J. Org.
Chem. 2008, 73, 1270–1281. (b) Sun, L.; Geng, X.; Geney, R.; Li, Y.;
Simmerling, C.; Li, Z.; Lauher, J. W.; Xia, S.; Horwitz, S. B.; Veith, J. M.;
Pera, P.; Bernacki, R. J.; Ojima, I. J. Org. Chem. 2008, 73, 9584–9593. (c) Shu,
C.; Zeng, X.; Hao, M.-H.; Wei, X.; Yee, N. K.; Busacca, C. A.; Han, Z.; Farina,
V.; Senanayake, C. H. Org. Lett. 2008, 10, 1303–1306. (d) Ramana, C. V.;
Khaladkar, T. P.; Chatterjee, S.; Gurjar, M. K. J. Org. Chem. 2008, 73, 3817–
3822. (e) Trost, B. M.; Dong, G.; Vance, J. A. J. Am. Chem. Soc. 2007, 129,
4540–4541. (f) Trost, B. M.; Yang, H.; Thiel, O. R.; Frontier, A. J.; Brindle,
C. S. J. Am. Chem. Soc. 2007, 129, 2206–2207. (g) Galletti, E.; Avramova,
S. I.; Renzulli, M. L.; Corelli, F.; Botta, M. Tetrahedron Lett. 2007, 48, 751–
754. (h) Smith, A. B.; Basu, K.; Bosanac, T. J. Am. Chem. Soc. 2007, 129,
14872–14874. (i) Reymond, S.; Cossy, J. Tetrahedron 2007, 63, 5918–5929. (j)
Fu¨rstner, A.; Nagano, T.; Mu¨ller, C.; Seidel, G.; Mu¨ller, O. Chem. Eur. J. 2007,
13, 1452–1462. (k) Fu¨rstner, A.; Nevado, C.; Waser, M.; Tremblay, M.; Chevrier,
C.; Teply´, F.; Aissa, C.; Moulin, E.; Mu¨ller, O. J. Am. Chem. Soc. 2007, 129,
9150–9161. (l) Larrosa, I.; Da Silva, M. I.; Go´mez, P. M.; Hannen, P.; Ko, E.;
Lenger, S. R.; Linke, S. R.; White, A. J. P.; Wilton, D.; Barrett, A. G. M. J. Am.
Chem. Soc. 2006, 128, 14042–14043.
(58) Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J. Tetrahedron
Lett. 1999, 40, 5161–5164.
(59) (a) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480–2482. (b) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660. (c)
Mancuso, A. J.; Swern, D. Synthesis 1981, 165–184.
(60) The sensitivity of the aldehyde 36 required buffering of the silica gel
with Et3N.
(57) For selected 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.
J. Org. Chem. Vol. 74, No. 4, 2009 1703

Helmboldt and Hiersemann
SCHEME 9. Attempted RCM
resulting ester with lithiated diethyl ethylphosphonate afforded
the ꢀ-keto phosphonate 41. Treatment of the aldehyde 36a with
the lithiated ꢀ-keto phosphonate 41 provided the R,ꢀ-unsaturated
ketone 42a as a single double-bond isomer. Successive removal
of the TMS and the TES protecting group and subsequent
oxidation of the secondary alcohol furnished the corresponding
C9-ketone. The TBS ether was then cleaved to provide the
desired diol 34a in a longest linear sequence of 15 scalable steps
from the acylated Evans auxiliary 7.
FIGURE 7. Retrosynthetic analysis based on a relay ring-closing
metathesis (RRCM).
SCHEME 10. Synthesis of the Aldehyde 50 as a 2/1 Mixture
of Double-Bond Isomers
With the requisite substrate 34a in our hands, the RCM to
the bicyclic jatrophane scaffold 44a was explored (Scheme 9).
For this purpose, the Grubbs catalysts 43a,61b62 and the Hoveyda
catalyst 43c63 were utilized in different solvents at different
temperatures (concentration of the substrate in the range of
(2-3) × 10-3 mol/L). Discouragingly, not even a trace of the
desired cyclization product 44a could be identified under the
reaction conditions depicted in Scheme 9. Varying amounts of
the starting material were recovered. Target-aimed structural
modifications at C3, C9, and C15 provided a small collection
of alternative substrates for the RCM (Scheme 9). Again, all
attempts to realize a RCM under various reaction conditions
were futile. Depending on the substrate structure, catalyst
structure, and reaction temperature, varying amounts of starting
material could be isolated. Interestingly, for the substituent
pattern R3 ) H, R9 ) (dO) and R15 ) H, the extent of the
decomposition of the starting material was dependent on the
catalyst loading (43b) and the reaction temperature. We
speculated that in this case, the initiation of the metathesis at
the sterically less encumbered C5/C5′ double bond takes place,
but the subsequent productive catalytic cycle can not be
completed. A possible remedy would be to direct the initiation
of the catalytic cycle to the presumably less reactive C6/C6‘
double bond which would make the more reactive C5/C5′ double
bond available for the subsequent ruthenacyclobutane formation.
Attempted C5/C6 Ring Closure by RRCM. The relay ring-
closing metathesis (RRCM) can be used to determine the
initiation side of the RCM by a structural modification of the
substrate.64 In the present case, our objective was to enforce
the formation of the ruthenium carbene complex 46 from the
carbene complex 47 by RCM under extrusion of cyclopen-
tene (Figure 7). Hence, the tetraene 48 would be offered as
substrate to the metathesis catalyst with the expectation that
the terminal double bond of the relay tether serves as the most
attractive initiation site. Applying the already successful olefi-
nation transform for the retrosynthesis of the tetraene 48
furnishes the known phosphonate 41 and the aldehyde 50 which
contains the required relay tether.
The synthesis of the aldehyde 50 was realized as depicted in
Scheme 10. Starting with the already synthesized alcohol 40a
(Scheme 7), the hydroxyl group was protected and the double
bond was oxidatively cleaved to provide the ketone 51. A Wittig
(64) (a) Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H.
J. Am. Chem. Soc. 2004, 126, 10210–10211. (b) Wang, X.; Bowman, E. J.;
Bowman, B. J.; Porco, J. A. Angew. Chem. Internat. Ed. 2004, 43, 3601–3605.
(c) Wallace, D. J. Angew. Chem., Int. Ed. 2005, 44, 1912–1915. (d) Roethle,
P. A.; Chen, I. T.; Trauner, D. J. Am. Chem. Soc. 2007, 129, 8960–8961. (e)
Sato, D.; Fujiwara, K.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2008, 49, 1514–
1517. (f) Marvin, C. C.; Voight, E. A.; Suh, J. M.; Paradise, C. L.; Burke, S. D.
J. Org. Chem. 2008, 73, 8452–8457. (g) Xie, Q.; Denton, R. W.; Parker, K. A.
Org. Lett. 2008, 10, 5345–5348.
(61) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118,
100–110.
(62) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953–956.
(63) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168–8179.
1704 J. Org. Chem. Vol. 74, No. 4, 2009

Synthetic Studies toward Jatrophane Diterpenes
SCHEME 11. Unsuccessful RRCM Attempts
SCHEME 12. Successful RCM Provides the
17-Norjatrophane 57
SCHEME 13. Successful RCM Provides
(+)-17-Norcharaciol 60
to support this hypothesis, we investigated the RCM of a
substrate lacking the C17 methyl group.
Total Synthesis of (+)-17-Norcharaciol (60) by RCM. The
required triene 34b (Figure 6) without the C17 methyl group
was synthesized analogous to 34a as outlined in Schemes 7 and
8. Triene 34b underwent RCM upon exposure to the metathesis
catalyst 43b (12.5 mol%) at 60 °C to afford the 17-norjatrophane
57 as a mixture of double-bond isomers (44%, E/Z ) 2/1) and
some starting material (18%) (Scheme 12). Application of the
metathesis catalyst 43c led to an inferior result, although no
attempts were made to optimize the reaction conditions.
Additional experiments were performed to test the respon-
siveness of the E/Z-selectivity of the RCM toward structural
changes at C3 (Scheme 13). Mitsunobu reaction of 34b provided
the (3S)-configured benzoate 58, whereas simple esterification
with 4-bromobenzoic acid made the (3R)-configured benzoate
58 available. Notably, when the triene (3S)-58 was treated with
Grubbs’ second-generation metathesis catalyst 43b (25 mol%,
unoptimized conditions) at 60 °C in 1,2-dichloroethane (DCE),
the norjatrophane (3S)-59 was observed as single E-configured
double bond isomer, albeit contaminated with an inseparable
impurity.66 Subsequent transesterification then provided 17-
norcharaciol 60. The beneficial effect of the benzoate group for
the E/Z selectivity of the metathesis became also apparent when
the diastereomeric ester (3R)-58 was treated with 43b (40 mol%,
unoptimized conditions). In the event, (3R)-59 was isolated as
single (E)-configured double bond isomer, albeit in lower yield,
with incomplete conversion and contaminated with inseparable
impurities.
olefination afforded the diene 53 as a 2/1 mixture of double
bond isomers. In situ deprotection of the primary hydroxyl group
and oxidation under Swern conditions delivered the desired
aldehyde 50.58
With the phosphonate 41 and the aldehyde 50 in hand, we
proceeded with their coupling which provided the tetraene 54
as single double bond isomer with respect to the newly generated
C12/C13 double bond (Scheme 11).
Stepwise removal of the silyl protecting groups and oxidation
of the C9 hydroxyl group afforded the tetraene 48 which was
subjected to the RRCM conditions using either the Grubbs II
(43b) or the Hoveyda catalyst (43c). Very discouragingly, not
a trace of the desired RRCM product could be isolated. Instead,
the relay tetherless triene 34a was observed in almost quantita-
tive yield,65 apparently formed by a RCM with release of
cyclopentene followed by an intermolecular cross metathesis
process. We were aware from previous experiences that the
result of the RCM is dependent on the structure of the substrate
(vide supra). Therefore, the benzoate 55 was synthesized and
treated with substoichiometric amounts of the metathesis catalyst
43b. As a result, we observed the formation of the triene 56
and a substantial decomposition of the starting material 55.
Initially, we attributed the failure of the RCM and RRCM to
the presence of the C17 methyl group and surmised that the
C17 methyl group may be responsible for the build-up of
unacceptable steric strain during the metathesis process. In order
We turned next our attention to the completion of the
synthesis of (-)-15-O-acetyl-3-O-propionyl-17-norcharaciol
(65) An increased reaction temperature led to a decreased yield of 34a.
Performing the RRCM in 1,2-dichlorethane at 80 °C with 43b (10 mol %) also
led to the formation of 34a (75%).
(66) The double-bond configuration was assigned on the basis of NOESY
experiments. An analogous result was obtained in toluene at 60°C.
J. Org. Chem. Vol. 74, No. 4, 2009 1705

Helmboldt and Hiersemann
TABLE 1. Selected NOESY Correlations of 15
SCHEME 14. Final Steps of Synthesis of
(-)-15-O-Acetyl-3-O-propionyl-17-norcharaciol 62
NOESY correlations of
15 (jatrophane numbering)
stereochemical
assignment
1
2
3
4
5
6
1-HRe (1.29 ppm) 5-CH (5.49 ppm)
cis: 1-HRe/-CHdC(CH3)-
4-CH (2.65 ppm) 2-CH (1.75-1.85 ppm) cis: 4-H/2-H
4-CH (2.65 ppm) 1-HSi (2.34 ppm)
4-CH (2.65 ppm) 14-CH2 (3.19 ppm)
3-CH (3.71 ppm) 1-HRe (1.29 ppm)
5-CH (5.49 ppm) 7-CH2 (4.01 ppm)
cis: 4-H/1-HSi
cis: 4-H/14-CH2
cis: 3-H/1-HRe
(5E)
The reaction mixture was stirred 15 min at -78 °C. A cooled (-78
°C) solution of the aldehyde 9 (2.87 g, 11.85 mmol, 1 equiv) was
then slowly added at -78 °C. After being stirred for 30 min at
-78 °C, the reaction mixture was diluted with saturated aqueous
NH4Cl solution and CH2Cl2. The phases were separated, and the
aqueous phase was extracted with CH2Cl2 (3×). The combined
organic layers were dried (MgSO4) and concentrated under reduced
pressure. Purification of the residue by chromatography delivered
the silyl enol ether 11a (4.84 g, 13.5 mmol, 95%) as a mixture of
double-bond isomers (E/Z > 10:1): Rf 0.7 (heptane/ethyl acetate
3/1); 1H NMR (300 MHz, CDCl3) δ -0.13 (s, 3H), -0.10 (s, 3H),
0.00 (s, 3H), 0.01 (s, 3H), 0.76 (s, 9H), 0.82 (s, 9H), 0.88 (d, J )
6.8 Hz, 3H), 1.53-1.58 (m, 3H), 3.02-3.15 (m, 1H), 3.63 (s, 3H),
3.78 (dd, J1 ) J2 ) 6.2 Hz, 1H), 5.23-5.50 (m, 2H), 5.27 (d, J )
10.7 Hz, 1 H), 5.84 (d, J ) 10.1 Hz, 1H of (Z)-11a); 13C NMR
(75.5 MHz, CDCl3) δ -5.0, -4.9, -4.1, 16.1, 17.6, 18.2, 25.6,
25.9, 38.3, 51.3, 77.4, 126.2, 128.3, 133.0, 139.6, 165.2; IR (thin
film on KBr) ν 1730, 2860-2960 cm-1. Anal. Calcd for
C22H44O4Si2: C, 61.63; H 10.34. Found: C, 61.51; H, 10.57.
Alcohol 15. To a solution of the aldeyhde 14 (803 mg, 1.54
mmol, 1 equiv) in toluene (15 mL) in a commercially available
sealed tube was added (1-ethoxycarbonylethylidene)triph-
enylphosphorane (1.11 g, 3.07 mmol, 2 equiv). The tube was sealed
with a Teflon screw-cap and placed into an oil bath at 130 °C for
5 d. The toluene was then removed at reduced pressure, the residue
redissolved in a heptane/ethyl acetate 10/1, and the solution filtered
through a plug of Celite. The filtrate was concentrated at reduced
pressure, and the crude product was purified by chromatography
(heptane to heptane/ethyl acetate 50/1) to afford the olefin
contaminated with an inseparable impurity. A small purified sample
for analytical purposes could be isolated: Rf 0.40 (heptane/ethyl
(62), the 17-desmethyl derivative of the naturally occurring
characiol diester 3b (Scheme 14). Cleavage of the benzoate in
(3S)-58 by transesterification followed by 1-[3-(dimethylami-
no)propyl]-3-ethylcarbodiimide67 (EDC)-mediated esterification
with propionic acid provided the triene 61 in moderate overall
yield (50%). Exposure of 61 to Grubbs’ second-generation
metathesis catalyst (43b, 5 × 2.5 mol %) furnished the
corresponding 17-norjatrophane in very good yield (75%). The
catalyst 43b was added as a solid in five equal portions, a portion
after each 1 h reaction period.68 With the 17-norjatrophane in
hand, it was straightforward to complete the synthesis of 62 by
acetylation of the tertiary hydroxyl group in the presence of
acetic anhydride and catalytic amounts of (CH3)3SiOTf.69
Notably, the reversal of the last two stepssacetylation first, then
RCMsled to lower yields, in particular with respect to the RCM
event.
Conclusion
We have reported studies toward the total synthesis of
∆5,6∆12,13 jatrophane diterpenoids. Key features of the synthesis
include (i) the homologation of an R-chiral aldehyde into a
γ-chiral R-keto ester, (ii) the diastereoselective uncatalyzed
intramolecular carbonyl ene reaction of an δ,ꢀ-unsaturated
R-keto ester to provide a densely functionalized cyclopentane
building block, and (iii) the formation of a 12-membered ring
by ring closing metathesis. The work culminated in the synthesis
of the non-natural 17-norjatrophane (-)-15-O-acetyl-3-O-pro-
pionyl-17-norcharaciol (62) in 20 steps and 4% yield along the
longest linear sequence. Although our efforts toward the
synthesis of the complete jatrophane core have not yet been
successful, the experiences and synthetic strategies described
herein should be useful for the design of alternate approaches
toward the jatrophane framework. This objective is currently
being pursued in our laboratory and will be reported in due
course.
1
acetat 5/1); H NMR (300 MHz, CDCl3) δ -0.16 (s, 3H), -0.07
(s, 3H), -0.05 (s, 3H), 0.00 (s, 3H), 0.76 (s, 9H), 0.81 (s, 9H),
1.00 (d, J ) 6.8 Hz, 3H), 1.20 (t, J ) 7.0 Hz, 3H), 1.26 (dd, J1 )
14.1 Hz, J2 ) 8.0 Hz, 1H), 1.75 (d, J ) 1.6 Hz, 3H), 1.70-1.89
(m, 1H), 2.31 (dd, J1 ) 13.8 Hz, J2 ) 10.2 Hz, 1H), 2.74 (dd, J1
) 10.7 Hz, J2 ) 9.7 Hz, 1H), 3.08 (d, J ) 8.8 Hz, 1H), 3.14 (d, J
) 8.7 Hz, 1H), 3.74 (s, 3H), 3.77 (dd, J1 ) J2 ) 9.1 Hz, 1H), 4.11
(q, J ) 7.1 Hz, 2H), 4.30 (d, J ) 11.4 Hz, 1H), 4.35 (d, J ) 11.7
Hz, 1H), 6.78-6.85 (m, 3H), 7.13-7.19 (m, 2H); 13C NMR (75.5
MHz, CDCl3) δ -4.4, -4.2, -2.4, 12.9, 14.2, 17.9, 18.4, 18.9,
25.8, 25.9, 40.3, 42.9, 54.6, 55.2, 60.2, 73.0, 74.8, 83.0, 83.9, 113.7,
129.2, 129.6, 130.2, 141.8, 159.1, 168.0; IR (film on KBr) ν 775,
835, 1110, 1250, 1510, 1710, 2860, 2930, 2950 cm-1; [R]25D +2.6
(c 1.55, CHCl3). Anal. Calcd for C33H58O6Si2: C, 65.30; H, 9.63.
Found: C, 65.21; H, 9.65.
To a solution of the contaminated olefin (774 mg, assumed 1.53
mmol, 1 equiv) in CH2Cl2 (15 mL) was added DIBAH (4.6 mL,
4.6 mmol, 1 M in CH2Cl2, 3 equiv) at -78 °C. The reaction mixture
was stirred for 30 min at -78 °C. Saturated aqueous potassium
sodium tartrate solution was then added, and the resulting mixture
was stirred at ambient temperature for 1 h. The phases were
separated, and the aqueous layer was extracted with CH2Cl2 (3×).
The combined organic phases were dried (MgSO4) and concentrated
at reduced pressure. Chromatographic purification (heptane to
heptane/ethyl acetate 20/1) delivered the allylic alcohol 15 (650
mg, 1.15 mmol, 75% from 14) as a colorless oil: Rf 0.37 (heptan/
ethyl acetate 3/1); COSY, HSQC, HMBC, and NOESY (Table 1)
methods were used to confirm the NMR peak assignments on the
Experimental Section
Silyl Enol Ether (E)-11a. To a solution of the phosphonate 10a32
(4.44 g, 14.22 mmol, 1.2 equiv) in THF (56 mL) at -78 °C was
added n-BuLi (5.55 mL, 2.35 M in hexanes, 13.03 mmol, 1.1 equiv).
(67) Sheehan, J.; Cruickshank, P.; Boshart, G. J. Org. Chem. 1961, 26, 2525–
2528.
(68) Nicola, T.; Brenner, M.; Donsbach, K.; Kreye, P. Org. Process Res.
DeV. 2005, 9, 513–515.
(69) Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G. G. A. J. Org.
Chem. 1998, 63, 2342–2347.
1706 J. Org. Chem. Vol. 74, No. 4, 2009

Synthetic Studies toward Jatrophane Diterpenes
basis of the jatrophane numbering; 1H NMR (500 MHz, CDCl3) δ
-0.06 (s, TBS-CH3, 3H), -0.01 (s, TBS-CH3, 3H), 0.02 (s, TBS-
CH3, 3H), 0.06 (s, TBS-CH3, 3H), 0.84 (s, TBS- 3 × CH3, 9H),
0.86 (s, TBS- 3 × CH3, 9H), 1.06 (d, J ) 6.9 Hz, 16-CH3, 3H),
1.29 (dd, J1 ) 14.0 Hz, J2 ) 8.0 Hz, 1-CH2, 1HRe), 1.65 (s, 17-
CH3, 3H), 1.75-1.85 (m, 2-CH, 1 H), 2.34 (dd, J1 ) 13.9 Hz, J2
) 10.4 Hz, 1-CH2, 1HSi), 2.65 (dd, J1 ) J2 ) 9.9 Hz, 4-CH, 1H),
3.17 (d, J ) 8.7 Hz, 14-CH2, 1H), 3.20 (d, J ) 8.7 Hz, 14-CH2,
1H), 3.71 (dd, J1 ) J2 ) 8.8 Hz, 3-CH, 1 H), 3.80 (s, -OCH3, 3
H), 4.01 (s, 7-CH2, 2 H), 4.36 (d, J ) 11.7 Hz, -OCH2-Ar-OCH3,
1 H), 4.42 (d, J ) 11.5 Hz, -OCH2-Ar-OCH3, 1 H), 5.49 (d, J )
10.1 Hz, 5-CH, 1 H), 6.87 (d, J ) 8.5 Hz, -OPMB, 2H), 7.23 (d,
J ) 8.5 Hz, -OPMB, 2H), no observable OH resonance; 13C NMR
(126.0 MHz, CDCl3) δ -4.3 (TBS-CH3), -4.0 (TBS-CH3), -2.4
(2 × TBS-CH3), 14.2 (17-CH3), 17.9 (TBS-C), 18.4 (TBS-C), 19.0
(16-CH3), 25.8 (3 × TBS-CH3), 25.9 (3 × TBS-CH3), 39.8 (2-
CH), 42.7 (1-CH2), 53.3 (4-CH), 55.2 (-Ar-OCH3), 69.4 (7-CH2),
72.9 (-OCH2-Ar-OCH3), 74.9 (14-CH2), 82.4 (15-C), 84.1 (3-CH),
113.6 (-OPMB- 2 × CHd), 125.4 (5-CHd), 129.1 (-OPMB-
2×CHd),130.4(-OPMB-Cd),137.0(6-Cd),159.0(-OPMB-Cd);
IR (thin film on KBr) ν 830, 1040, 1090, 1250, 1510, 2860, 2930,
(film on KBr) ν 1100, 1250, 2850, 2900, 2950 cm-1. Anal. Calcd
for C32H58O4Si2: C, 68.27; H, 10.38. Found: C, 68.36; H, 10.31.
Vinyl Iodide 25a. To a solution of the alkyne 24a (103 mg,
0.122 mmol, 1 equiv) in THF (5 mL) in a commercially available
glass pressure tube was added chlorobis(cyclopentadienyl)hy-
dridozirconium(IV) (158 mg, 0.61 mmol, 5 equiv). The tube was
sealed with a Teflon screw-cap, heated in an oil bath (60 °C) for
1.5 h, and then cooled to ambient temperature. To the dark purple
reaction mixture was added I2 (47 mg, 0.184 mmol, 1.5 equiv). A
change of color from purple to yellow to brownish was observed.
After TLC indicated the complete consumption of the zirconocene
intermediate (Rf 0.4 heptane/ethyl acetate 5/1), the reaction was
quenched by the addition saturated aqueous NaHCO3 solution and
CH2Cl2. The layers were separated, the organic phase was extracted
with CH2Cl2 (3×), and the combined organic layers were dried
(MgSO4), concentrated at reduced pressure, and then purified by
chromatography (heptane to heptane/ethyl acetate 50/1) to provide
the vinyl iodide 25a (115 mg, 0.119 mmol, 97%, 1:1 mixture of
epimers at C9) as a colorless oil. 25a as a 1:1 mixture of C9
1
epimers: Rf 0.5 (heptane/ethyl acetate 10/1); H NMR (500 MHz,
CDCl3) δ -0.06 (s, 3 + 3H), -0.03 (s, 3 + 3H), 0.01 (s, 3 + 3H),
0.04 (s, 3 + 3H), 0.82-0.88 (m, 24 + 24H), 1.04 (d, J ) 6.6 Hz,
3 + 3H), 1.09 (br.s, 21 + 21H), 1.23-1.33 (m, 1 + 1H), 1.44-1.54
(m, 1 + 1H), 1.57 (s, 3 + 3H), 1.65-1.82 (m, 2 + 2H), 1.86-1.98
(m, 1 + 1H), 1.98-2.10 (m, 1 + 1H), 2.18-2.27 (m, 1 + 1H),
2.29-2.36 (m, 1 + 1H), 2.35 (s, 3 + 3H), 2.59 (dd, J1 ) J2 ) 9.8
Hz, 1 + 1H), 3.12-3.21 (m, 2 + 2H), 3.42-3.50 (m, 1 + 1H),
3.69 (dd, J1 ) J2 ) 8.8 Hz, 1 + 1H), 3.80 (s, 3 + 3H), 4.34 (d, J
) 11.4 Hz, 1 + 1H), 4.40 (d, J ) 11.4 Hz, 1H), 4.41 (d, J ) 11.4
Hz, 1H), 5.19 (d, J ) 9.1 Hz, 1 + 1H), 6.23 (t, J ) 7.7 Hz, 1 +
1 Hz), 6.86 (d, J ) 8.5 Hz, 2 + 2H), 7.22 (d, J ) 8.2 Hz, 2 + 2H);
13C NMR (126 MHz, CDCl3) δ -4.2, -4.2, -4.1, -4.0, -2.4,
-2.4, 13.7, 14.1, 17.1, 17.3, 18.0, 18.5, 18.5, 19.3, 22.7, 22.8, 23.7,
25.9, 26.0, 27.7, 31.9, 32.2, 38.5, 38.9, 39.1, 39.6, 40.2, 40.3, 42.5,
53.5, 53.6, 55.2, 72.9, 74.8, 74.8, 81.1, 81.5, 82.6, 84.3, 94.5, 113.6,
123.0, 123.2, 129.1, 130.5, 137.5, 138.9, 159.0; IR (film on KBr)
ν 1100, 1500, 2850-2900 cm-1. Anal. Calcd for C49H91IO5Si3: C,
60.58; H, 9.44. Found: C, 60.27; H, 9.75.
2950 cm-1; [R]30 +4.7 (c 1.6, CHCl3). Anal. Calcd for
D
C31H56O5Si2: C, 65.91; H, 9.99. Found: C, 66.06; H, 10.13.
Alkyne 18. To a cooled (-78 °C) solution of the iodide 16 (405
mg, 0.59 mmol, 1 equiv) in hexanes (10 mL) and Et2O (6.5 mL)
were added t-BuLi (0.96 mL, 1.29 mmol, 1.35 M in pentane, 2.2
equiv) and, immediately, a cooled (-78 °C) solution of the aldehyde
17 (146 mg, 1.18 mmol, 2 equiv) in hexanes (1 mL). After being
stirred for 5 min at -78 °C, the reaction mixture was diluted with
saturated aqueous NH4Cl solution and CH2Cl2. The phases were
then separated, the aqueous layer was extracted with CH2Cl2 (3×),
the combined organic phases were dried (MgSO4) and concentrated
at reduced pressure, and the residue was purified by chromatography
(heptane to heptane/ethyl acetate 20/1) to provide the alkyne 18
(337 mg, 0.49 mmol, 83%, 1:1 mixture of C9 epimers) and the
protodeiodinated substrate (50 mg, 0.09 mmol, 15%). Alkyne 18
was obtained as a 1:1 mixture of C9 epimers: Rf 0.29 (heptane/
1
ethyl acetate 5/1); H NMR (300 MHz, CDCl3) δ -0.04 (s, 3 +
3H), 0.00 (s, 3 + 3H), 0.03 (s, 3 + 3H), 0.05 (s, 3H), 0.06 (s, 3H),
0.85 (s, 9 + 9H), 0.88 (s, 9 + 9H), 0.93 (s, 3H), 0.94 (s, 3H), 0.96
(s, 3H), 0.97 (s, 3H), 1.06 (d, J ) 6.8 Hz, 3H), 1.06 (d, J ) 6.8
Hz, 3H), 1.24-1.33 (m, 1 + 1H), 1.38-1.48 (m, 1 + 1H), 1.60
(d, J ) 1.0 Hz, 3H), 1.62 (d, J ) 1.0 Hz, 3H), 1.63-1.80 (m, 1 +
1H), 1.80 (q, J ) 2.5 Hz, 3 + 3H), 1.97-2.40 (m, 6 + 6H), 2.61
(dd, J1 ) J2 ) 9.7 Hz, 1H), 2.62 (dd, J1 ) J2 ) 9.9 Hz, 1H),
3.13-3.22 (m, 2 + 2H), 3.35-3.45 (m, 1 + 1H), 3.65-3.75 (m,
1 + 1H), 3.82 (s, 3 + 3H), 4.34-4.45 (m, 2 + 2H), 5.26 (d, J )
9.4 Hz, 1H), 5.28 (d, J ) 9.4 Hz, 1H), 6.88 (d, J ) 8.4 Hz, 2 +
2H), 7.22-7.27 (m, 2 + 2H), no observable OH resonance; 13C
NMR (75.5 MHz, CDCl3) δ -4.2, -4.1, -4.0, -2.4, 3.5, 17.0,
17.1, 18.0, 18.5, 19.1, 19.2, 22.3, 22.4, 23.7, 23.8, 25.9, 26.0, 29.2,
29.4, 29.5, 29.7, 37.2, 38.0, 38.1, 39.6, 39.7, 42.5, 42.7, 53.6, 53.7,
55.3, 72.9, 75.0, 75.1, 77.5, 77.0, 77.8, 78.7, 82.5, 84.1, 84.2, 113.6,
123.5, 123.7, 129.1, 129.2, 130.5, 137.3, 137.8, 159.1; IR (film on
KBr) ν 830, 1250, 1510, 2850-2950 cm-1. Anal. Calcd for
C40H70O5Si2: C, 69.92; H, 10.27. Found: C, 69.75; H, 10.27.
Protodeiodinated substrate: Rf 0.55 (heptane/ethyl acetate 5/1); 1H
NMR (300 MHz, CDCl3) δ -0.08 (s, 3H), -0.04 (s, 3H), 0.00 (s,
3H), 0.02 (s, 3H), 0.82 (s, 9H), 0.85 (s, 9H), 0.98 (t, J ) 7.4 Hz,
3H), 1.03 (d, J ) 6.8 Hz, 3H), 1.25 (dd, J1 ) 13.9 Hz, J2 ) 7.6
Hz, 1H), 1.56 (d, J ) 1.1 Hz, 3H), 1.69-1.85 (m, 1H), 1.99 (q, J
) 7.2 Hz, 2H), 2.32 (dd, J1 ) 13.9 Hz, J2 ) 10.6 Hz, 1H), 2.58
(dd, J1 ) J2 ) 9.9 Hz, 1H), 3.13 (d, J ) 8.5 Hz, 1H), 3.18 (d, J )
8.5 Hz, 1H), 3.68 (dd, J1 ) 9.5 Hz, J2 ) 8.3 Hz, 1H), 3.79 (s, 3H),
4.33 (d, J ) 11.7 Hz, 1H), 4.40 (d, J ) 11.5 Hz, 1H), 5.18 (dd, J1
) 10.1 Hz, J2 ) 1.2 Hz, 1H), 6.85 (d, J ) 8.7 Hz, 2H), 7.21 (d, J
) 8.6 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) δ -4.2, -4.1, -2.4,
12.4, 16.9, 18.0, 18.5, 19.3, 25.9, 26.0, 32.6, 39.6, 42.6, 53.5, 55.2,
72.9, 74.8, 82.7, 84.3, 113.6, 122.0, 129.1, 130.6, 138.8, 159.0; IR
Tetraene 54. To a THF (8 mL) solution of the phosphonate 41
(2.16 g, 4.14 mmol, 2 equiv) in a commercially available glass
pressure tube at 0 °C was added n-BuLi (1.5 mL, 2.4 M in hexanes,
3.62 mmol, 1.75 equiv), and the reaction mixture was stirred for 5
min. A solution of the aldehyde 50 (759 mg, 2.07 mmol, 1 equiv)
in THF (4 mL) was added, and the tube was sealed with a Teflon
screw-cap and heated in an oil bath (70 °C) for 12 h. The reaction
mixture was then diluted with saturated aqueous NH4Cl solution
and CH2Cl2. The layers were separated, the aqueous phase was
extracted with CH2Cl2 (3×), and the combined organic layers were
dried (MgSO4) and concentrated at reduced pressure. The residue
was then purified by chromatography (hexanes to hexanes/ethyl
acetate 1/1) to deliver the tetraene 54 (1.17 g, 1.60 mmol, 74%,
1:1 mixture of C9 epimers and 2:1 mixture of C6 double bond
isomers) as a yellow oil. The unreacted phosphonate 41 (539 mg,
1.03 mmol) was chromatographically separable and reisolated. 54,
as mixture of stereoisomers: Rf 0.93 (hexanes/ethyl acetate 10/1);
1H NMR (500 MHz, CDCl3), only diagnostic resonances are
reported, δ -0.04 (s, 3H), 0.01 (s, 3H), 0.02-0.04 (m, 9H),
0.60-0.67 (m, 6H), 0.79-0.81 (m, 3H), 0.83 (s, 9H), 0.85-0.87
(m, 3H), 0.92-1.00 (m, 9H), 1.01-10.4 (m, 3H), 1.23-2.23 (m,
20H), 2.45-2.50 (m, 1 H), 2.68-2.75 (m, 1H), 3.21-3.32 (m, 1H),
3.45-3.50 (m, 1H), 4.90-5.02 (m, 3H), 5.08-5.15 (m, 2H),
5.75-5.92 (m, 2H), 6.80-6.86 (m, 1H); 13C NMR (126 MHz,
CDCl3), only diagnostic resonances are reported, δ -4.0, -3.3,
1.9, 1.9, 4.4, 5.7, 6.8, 7.2, 13.0, 17.9, 18.0, 22.6, 22.8, 23.5, 23.8,
25.9, 27.3, 27.4, 29.1, 29.3, 30.5, 31.5, 33.4, 37.3, 37.5, 37.9, 39.7,
39.7, 40.6, 40.6, 45.4, 45.4, 62.5, 81.2, 81.3, 81.7, 81.8, 83.7, 86.9,
86.9, 114.3, 114.4, 118.6, 118.6, 124.3, 124.9, 134.2, 134.3, 135.7,
136.3, 136.3, 138.9, 139.0, 142.4, 142.4, 204.6, 204.6; IR (film on
J. Org. Chem. Vol. 74, No. 4, 2009 1707

Helmboldt and Hiersemann
KBr) ν 840, 1250, 1700, 2900, 2950 cm-1. Anal. Calcd for
C42H80O4Si3: C, 68.79; H, 11.00. Found: C, 68.85; H, 11.00.
(+)-17-Norcharaciol (+)-60. A solution of the benzoate (3S)-
59 (17.8 mg, 0.035 mmol, 1 equiv) and finely ground K2CO3 (5
mg, 0.036 mmol, 1 equiv) in MeOH (3 mL) was stirred at ambient
temperature for 48 h and then diluted with saturated aqueous NH4Cl
solution and CH2Cl2. The layers were separated, the organic phase
was extracted with CH2Cl2 (3×), and the combined organic layers
were dried (MgSO4) and concentrated at reduced pressure. Chro-
matographic purification (hexanes/ethyl acetate 20/1 to 2/1) of the
residue afforded (+)-60 (6.8 mg, 0.021 mmol, 60%) as yellow oil:
Rf 0.32 (hexanes/ethyl acetate 2/1); COSY, HSQC, HMBC, and
NOESY methods were used to confirm the NMR peak assignments
13C NMR (126 MHz, CDCl3) δ 12.9 (20-CH3), 14.0 (16-CH3), 24.7
(18-CH3 or 19-CH3), 25.3 (18-CH3 or 19-CH3), 27.2 (7-CH2), 35.7
(8-CH2), 38.9 (2-CH), 40.5 (11-CH2), 48.0 (10-C), 48.1 (1-CH2),
59.3 (4-CH), 81.3 (3-CH), 92.0 (15-C), 127.4 (6-CHd), 134.3 (5-
CHd), 136.7 (13-Cd), 144.8 (12-CHd), 202.1 (14-CdO), 215.3
(9-CdO); selected NOESY crosspeaks 20-CH3, (1.72 ppm)/11-CH2
(2.44 ppm and 2.52 ppm) f (12E), 1-HSi (3.09 ppm)/3-H (3.97
ppm) f cis: 1-HSi and 3-H, no observable NOESY crosspeak 5-H
(5.81 ppm)/6-H (5.18 ppm) f (5E); IR (film on KBr) ν 1000, 1050,
1100, 1650, 1700, 2900, 3450 cm-1; [R]25 +21 (c 0.3, CHCl3).
D
Anal. Calcd for C19H28O4: C, 71.22; H, 8.81. Found: C, 70.90; H,
8.64.
1
Acknowledgment. Financial support from the DFG (HI 628/
6) is gratefully acknowledged. We thank Prof. Dr. Bernd
Schmidt (Universita¨t Potsdam) for insightful discussions con-
cerning the RCM and for bringing the RRCM to our attention.
based on the jatrophane numbering: H NMR (500 MHz, CDCl3)
δ 1.08 (d, J ) 6.8 Hz, 16-CH3, 3H), 1.15 (s, 18-CH3 or 19-CH3,
3H), 1.18 (s, 18-CH3 or 19-CH3, 3H), 1.50 (dd, J1 ) 13.9 Hz, J2 )
11.0 Hz, 1-CH2, 1HRe), 1.72 (s, 20-CH3, 3H), 1.98-2.09 (m, 2-CH,
1H), 2.11-2.22 (m, 4-CH, 1H and 7-CH2, 1H and 8-CH2, 1H),
2.44 (ddd, J1 ) 17.3 Hz, J2 ) 5.4 Hz, J3 ) 1.2 Hz, 11-CH2, 1H),
2.52 (dd, J1 )17.4 Hz, J2 ) 7.2 Hz, 11-CH2, 1H), 2.70-2.77 (m,
7-CH2, 1H and 8-CH2, 1H), 3.04 (br s, -OH, 1H), 3.09 (dd, J1 )
13.9 Hz, J2 ) 9.2 Hz, 1-CH2, 1HSi), 3.97 (dd, J1 ) J2 ) 3.1 Hz,
3-CH, 1H), 5.18 (ddd, J1 ) 14.9 Hz, J2 ) 9.9 Hz, J3 ) 4.7 Hz,
6-CHd, 1H), 5.81 (dd, J1 ) 15.4 Hz, J2 ) 9.9 Hz, 5-CHd, 1H),
6.91-6.95 (m, 12-CHd, 1H), only one observable OH resonance;
Supporting Information Available: Experimental proce-
dures and spectral and analytical data for new compounds not
given in the Experimental Section; copies of 1H and 13C NMR
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO802581G
1708 J. Org. Chem. Vol. 74, No. 4, 2009