Jatrophane diterpenes: Preparation of the western fragment of pl-3

Article abstract of DOI:10.1002/ejoc.201301616

Jatrophane diterpenes are structurally intriguing natural products with promising biological properties. Herein, the synthesis of the western fragment of the Euphorbiaceae constituent Pl-3 starting from (1R,5S)-bicyclo[3.2.0]hept- 2-en-6-one is described. Key steps in the sequence include a Baeyer-Villiger oxidation, an iodolactonization reaction, and the installation of the northern side chain through the addition of a lithiated vinyl bromide. The overall efficiency of the route is increased by taking advantage of latent symmetry. The synthesis of the western fragment of Pl-3 is developed by taking advantage of the latent symmetry in an intermediate; both enantiomers are thus converted into the desired substrate. Key steps of the synthesis include a Baeyer-Villiger oxidation, an iodolactonization reaction, and the addition of a vinyllithium species to the completed cyclopentane moiety of the natural product.

Full text of DOI:10.1002/ejoc.201301616

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301616
Jatrophane Diterpenes: Preparation of the Western Fragment of Pl-3
Christoph Lentsch,[a] Rita Fürst,[a] Johann Mulzer,[a] and Uwe Rinner*[a]
Keywords: Natural products / Total synthesis / Medicinal chemistry / Terpenoids / Oxidation / Lithium
Jatrophane diterpenes are structurally intriguing natural
products with promising biological properties. Herein, the
synthesis of the western fragment of the Euphorbiaceae con-
stituent Pl-3 starting from (1R,5S)-bicyclo[3.2.0]hept-2-en-6-
one is described. Key steps in the sequence include a
Baeyer–Villiger oxidation, an iodolactonization reaction, and
the installation of the northern side chain through the ad-
dition of a lithiated vinyl bromide. The overall efficiency of
the route is increased by taking advantage of latent sym-
metry.
Hohmann and co-workers from Euphorbia platyphyllos, a
glabrous or pubescent annual plant that occurs mainly in
the southern parts of Europe.[6] Recently, we presented a
short and general approach toward five-membered ring syn-
thons suitable for the preparation of various jatrophane di-
terpenes.[5h] Herein, we report a conceptually different and
improved route toward the western fragment of Pl-3.
As outlined in the retrosynthetic analysis (Scheme 1), a
ring-closing metathesis (RCM) reaction is intended to be
the final key step to close the 12-membered macrocycle. The
RCM precursor is envisaged to be prepared by a Nozaki–
Hiyama–Kishi (NHK) coupling reaction of aldehyde 2 and
vinyl iodide 3 with subsequent reductive alkene shift (C6–
C17 to C5–C6 double bond, jatrophane numbering).[7] This
strategy takes advantage of the comprehensive work per-
formed by Hiersemann and co-workers on their way to
(–)-15-O-acetyl-3-O-propionylcharaciol. The Hiersemann
group was able to demonstrate that, although the C12–C13
ring closure can be accomplished by a RCM reaction, this
reaction is not feasible for the elaboration of the sterically
congested trisubstituted C5–C6 double bond.[4e,5d] The
Introduction
The genus Euphorbia belongs to the Euphorbiaceae fam-
ily and is considered to be one of the largest genera in the
plant kingdom, consisting of more than 2000 known spe-
cies.[1] Members of this plant family, also commonly re-
ferred to as spurges, are endemic in tropical and subtropical
regions but can also be found in temperate climate zones.
The milky latex of Euphorbia plants is a rich source of
structurally complex and compelling terpene-based natural
products. Since the isolation of jatrophone in 1970,[2] more
than 300 different compounds have been isolated. The
chemical constituents, mostly diterpenes from the tigliane,
ingenane, daphnane, and jatrophane families, show a wide
range of biological activities. Among those, multidrug resis-
tance modulating properties, as well as antiproliferative ac-
tivity, particularly found in jatrophane diterpenes, are most
important.[3]
Despite the fascinating structural features and diverse
biological properties of the large number of Euphorbiaceae
constituents isolated so far, only a few have been synthe-
sized up to now.[4] In recent years, various synthetic strate-
gies toward different jatrophane diterpenes have been pre-
sented.[5] Prompted by the pharmacological properties of
jatrophane diterpenes as well as the challenging structural
features of the terpene-based natural products, we concen-
trate on the synthesis of Pl-3 (1). The jatrophane diterpene
Pl-3 consists of a highly oxygenated trans-fused bicy-
clo[10.3.0]pentadecane skeleton and was isolated in 2003 by
[a] Institute of Organic Chemistry, University of Vienna,
Währinger Straße 38, 1090 Vienna, Austria
E-mail: uwe.rinner@univie.ac.at
http://rinner-group.univie.ac.at
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301616.
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH &
Co. KGaA. This is an open access article under the terms of
the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the
original work is properly cited.
Scheme 1. Retrosynthetic analysis (TIPS = triisopropylsilyl, PMB
= p-methoxybenzyl, TBS = tert-butyldimethylsilyl).
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C. Lentsch, R. Fürst, J. Mulzer, U. Rinner
SHORT COMMUNICATION
elaboration of aldehyde 2 from intermediate 4 requires the by esterification with chloracetic anhydride and subsequent
removal of carbon C6, which will be accomplished through enzymatic resolution of chloroacetate rac-7 (Scheme 2, a).[8]
elimination and subsequent ozonolytic cleavage, as pre- Oxidation of the alcohol functionality in 8 (Scheme 2, b)
viously demonstrated by the Hiersemann group.[4e] Cy- delivered enantiomerically pure bicyclic ketone 6, which
clopentyl fragment 4 should become accessible from bicy- was converted into lactone 9 by treatment of the alkene
clic ketone 6 by Baeyer–Villiger oxidation, an iodolacton- with aqueous hydrogen peroxide in acetic acid. Lactone 9
ization, and a vinyllithium coupling reaction as key steps.
was obtained as the sole product of the Baeyer–Villiger oxi-
dation in excellent yield.[9]
Next, we turned our attention to the functionalization of
the double bond. As iodolactonization was identified as the
most feasible procedure to elaborate the stereochemical
pattern present in the natural product, lactone 9 was al-
lowed to react with iodine under different reaction condi-
tions. The iodolactonization showed a distinct pH-depend-
ent product formation. Whereas desired iodolactone 10 was
favored at pH 6, 11 was isolated as major product if the pH
was higher than 8. The inseparable mixture of iodolactones
could be easily separated by flash column chromatography
after formation of corresponding silyl ethers 12 and 13.[10]
As the originally envisioned direct methylation of the
iodide could not be achieved, we decided to follow a slightly
modified approach and targeted the installation of the
methyl functionality by conjugate addition. Thus, cyclopen-
tene 14 was prepared in quantitative yield through DBU-
mediated elimination of the iodide in 13. At that point, the
great advantage of the latent symmetry in cyclopentene 14
became evident, as the mirror plane present in the substrate
(shown in unprotected intermediate 15, Scheme 3) allowed
the conversion of antipodal alcohol ent-8 into enantiomeri-
cally pure lactone 14 (Scheme 3). The “enantiomeric
switch” was accomplished simply by adjusting the pH dur-
ing the iodolactonization reaction. As a consequence of the
symmetry, both enantiomers of alcohol 8 were efficiently
converted into lactone 14.
Results and Discussion
The synthesis of 14 commenced with enantiomerically
pure bicyclo[3.2.0]hept-2-en-6-ol (8), as outlined in
Scheme 2. This building block became available on a
multigram scale from racemic ketone rac-(6) through dia-
stereoselective reduction with sodium borohydride, followed
Reduction of the lactone functionality in 14 with lithium
aluminum hydride afforded diol 16 in excellent yield
(Scheme 4). Next, silylation of the primary hydroxy func-
tionality, followed by allylic oxidation delivered enone 18,
Scheme 2. Preparation of lactone 14 (py = pyridine, MTBE =
methyl tert-butyl ether, Tf = trifluoromethanesulfonyl, DBU = 1,8-
diazabicyclo[5.4.0]undec-7-ene).
Scheme 3. Advantage of latent symmetry in the synthesis of 14.
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Jatrophane Diterpenes: Preparation of the Western Fragment of Pl-3
which served as the substrate for the conjugate addition re-
action. Although enone 18 was also accessible in compar-
able yield by performing the reaction sequence in reverse
order, that is, allylic oxidation followed by silylation with
TBS-triflate (via 17), the initial route was favored because
of the lower cost of the reagents. Selective 1,4-addition of a
methyl cuprate afforded five-membered ring synthon 5 in
excellent yield as a single isomer. The preparation of 5 is
easily scalable and the short reaction sequence allowed per-
fect control of all stereogenic centers.
Scheme 4. Preparation of ketone 5.
Scheme 5. Synthesis of the western fragment of Pl-3 (CSA = cam-
phorsulfonic acid, DIBAL-H = diisobutylaluminum hydride, 2,2-
DMP = 2,2-dimethoxypropane, PPTS = pyridinium para-toluene-
sulfonate).
Vinyl bromide 21 was prepared in five steps from com-
mercially available (S)-(+)-Roche ester (19), as shown in
Scheme 5. Protection of the hydroxy functionality as a
PMB ether was followed by a reduction/oxidation sequence
to access the corresponding aldehyde. Next, C1 elongation
with TMS-diazomethane afforded alkyne 20 in good overall
yield. Vinyl bromide 21 was isolated after regioselective hy-
droalumination catalyzed by nickel catalyst 25 and subse-
quent addition of N-bromosuccinimide (NBS), following
Hoveyda’s protocol.[11]
Alkylation of ketone 5 with lithiated vinyl bromide 21
proved to be a tedious task. Whereas the addition of vinyl-
magnesium bromide as test substrate afforded the corre-
sponding tertiary alcohol in nearly quantitative yield, de-
sired product 22 was not obtained by employing the Grig-
nard reagent derived from vinyl bromide 21. Reaction of 21
with sodium naphthalide and coupling under Barbier-type
conditions also did not solve the problem. Next, bromide
21 was converted into the corresponding boronate and em-
ployed in transition-metal-catalyzed coupling reactions,
also without success. Finally, the problem was solved upon
lithiation of bromide 21 with tBuLi in a solvent mixture
of pentane/diethyl ether in a ratio of 3:2, followed by slow
addition of ketone 5 to the lithiated species. Desired adduct
22 was obtained in 67% yield as a 3:1 diastereomeric mix-
ture, favoring the desired isomer. A detailed discussion of
all coupling attempts is provided in the Supporting Infor-
mation.
stereomeric ratio. The synthesis of the western fragment of
Pl-3 was concluded after protection of 23 as an acetonide
with concomitant cleavage of the primary silyl ether and
protection of the resulting primary alcohol as a ketal. Fi-
nally, intermediates 24 and 26 (prepared through acetonide
protection of the undesired diastereomeric diol, which was
afforded after reduction of ozonolysis product of 22; see the
Supporting Information) served to unambiguously define
the relative relationship of all stereogenic centers through
NOE correlation studies, as outlined in Figure 1.
Figure 1. NOE correlations in cyclopentanes 24 and 26.
Next, ozonolytic cleavage of the exomethylene function-
ality in the presence of Sudan III as indicator to prevent
benzylic oxidation of the PMB protecting group was fol-
lowed by selective reduction with sodium borohydride in
Conclusions
Summarizing, the synthesis of the western fragment of
ethanol, and advanced diol 23 was isolated in a 3.4:1 dia- Pl-3 was achieved in a short and stereoselective manner.
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C. Lentsch, R. Fürst, J. Mulzer, U. Rinner
SHORT COMMUNICATION
was quenched by the addition of a saturated aqueous solution of
NH4Cl (20 mL). The layers were separated, and the aqueous phase
was extracted with EtOAc (3 ϫ 20 mL). The combined organic
layer was washed with brine (50 mL), dried with MgSO4, filtered,
and concentrated under reduced pressure. The crude product was
purified by flash column chromatography (hexane/EtOAc, 40:1) to
afford 22 (0.237 g, 50%) as a colorless oil with the corresponding
C1 epimer (S10, see Supporting Information) as a side product
(80 mg, 17%). Note: The exact ratio of the solvents is essential for
the success of this reaction. Et2O and pentane, freshly distilled from
sodium, were mixed in a 3:2 ratio, and this solvent mixture was
stored over molecular sieves (3 Å) prior to use. 1H NMR
(400 MHz, CDCl3): δ = 7.27–7.24 (m, 2 H), 6.89–6.85 (m, 2 H),
5.28 (s, 1 H), 4.91 (s, 1 H), 4.48 (d, J = 11.6 Hz, 1 H), 4.38 (d, J =
11.6 Hz, 1 H), 4.11 (d, J = 3.8 Hz, 1 H), 4.00 (s, 1 H), 3.80 (s, 3
H), 3.69 (ddd, J = 9.8, 6.9, 4.7 Hz, 1 H), 3.63–3.57 (m, 1 H), 3.46
(dd, J = 9.1, 4.9 Hz, 1 H), 3.28 (dd, J = 9.1, 9.1 Hz, 1 H), 2.44–
2.23 (m, 2 H), 2.08 (ddd, J = 10.0, 3.3, 3.3 Hz, 1 H), 1.85 (dddd, J
= 14.4, 9.8, 5.0, 4.9 Hz, 1 H), 1.63–1.57 (m, 1 H), 1.61 (dd, J =
13.9, 3.3 Hz, 1 H), 1.15 (d, J = 6.8 Hz, 3 H), 1.13–1.09 (m, 21 H),
0.98 (d, J = 7.1 Hz, 3 H), 0.88 (s, 9 H), 0.03 (s, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 159.24 (C), 153.93 (C), 131.05 (C),
129.25 (CH), 113.85 (CH), 109.31 (CH2), 86.17 (C), 83.27 (CH),
75.91 (CH2), 72.72 (CH2), 62.15 (CH2), 55.41 (CH3), 47.86 (CH2),
45.35 (CH), 40.17 (CH), 34.81 (CH), 26.12 (CH3), 25.41 (C), 20.80
(CH), 20.42 (CH), 18.30 (CH3), 12.72 (CH), –5.16 (CH3) ppm.
HRMS (ESI): calcd. for C36H66NaO5Si2 [M + Na]+ 657.4346;
found 657.4332Ϯ5 ppm. [α]2D0 = +3.7 (c = 0.81, CHCl3). IR (ATR):
Importantly, the overall efficiency of the route was greatly
improved by taking advantage of the latent symmetry pres-
ent in lactone 14, which allowed the use of both enantio-
meric forms of bicyclic alcohol 8 as a starting material for
the preparation of 24. The utilization of 24 in the prepara-
tion of Pl-3 is currently under investigation, and further re-
sults will be reported in due course.
Experimental Section
(3aR,6aS)-3,3a,6,6a-Tetrahydro-2H-cyclopenta[b]furan-2-one
(9):[9,12] To a solution of 6 (9.76 mL, 92 mmol, 1.0 equiv.) in acetic
acid (237 mL) and water (26 mL) was added a solution of H2O2
(30 % in water, 22.7 mL, 222 mmol, 2.4 equiv.) in acetic acid
(195 mL) and water (22 mL) at 0 °C. The mixture was stirred for
24 h at 0 °C before water (200 mL) was added. The crude product
was extracted with CH2Cl2 (6ϫ 200 mL), and the combined or-
ganic extract was washed with aqueous Na2SO3 (10%, 200 mL)
and saturated NaHCO3 (600 mL). Note: Vigorous formation of
CO2 was observed. The workup must be performed with great care!
The organic layer was dried with MgSO4 and reduced in vacuo.
The product was purified by kugelrohr (bulb-to-bulb) distillation
to afford 9 (10.2 g, 88%) as a white solid. 1H NMR (400 MHz,
CDCl3): δ = 5.80–5.78 (m, 1 H), 5.59–5.57 (m, 1 H), 5.15–5.11 (m,
1 H), 3.53–3.49 (m, 1 H), 2.80–2.71 (m, 3 H), 2.47–2.42 (m, 1 H)
ppm. [α]2D0 = –102.3 (c = 1.03, CHCl3), m.p. 42–43 °C.
ν = 3494, 2954, 2866, 2360, 2341, 1716, 1613, 1586, 1540, 1513,
˜
(3aS,4S,6S,6aS)-4-Hydroxy-6-iodohexahydro-2H-cyclopenta[b]-
furan-2-one (10):[10] Lactone 9 (1.0 g, 8.06 mmol, 1.0 equiv.) was
added to a solution of NaOH (0.80 g, 20 mmol, 2.48 equiv.) in
water (41 mL). After stirring for 30 min at room temperature, the
resulting homogeneous solution was cooled to 0 °C and HCl
(32 wt.-% in water, 1.9 mL, 19.7 mmol, 2.44 equiv.) was added. Af-
ter stirring for approximately 30 s, pH 6 was obtained by the ad-
dition of dry ice. A solution of KI (12.04 g, 72.5 mmol, 9.0 equiv.)
and I2 (6.13 g, 24.17 mmol, 3.0 equiv.) in water (21 mL) was added
in one portion. The mixture was allowed to stir for 24 h between 0
and 5 °C before the reaction mixture was diluted with CH2Cl2
(150 mL) and quenched by the addition of solid Na2SO3 (addition
until a clear yellow solution over a white precipitate was observed).
The resulting colorless solution was saturated with Rochelle’s salt
and extracted exhaustively with CH2Cl2. To quantitatively transfer
the reaction product into the organic phase, the mixture was ex-
tracted at least 10 times (80 mL CH2Cl2 each time, progress was
monitored by TLC analysis). The combined organic layer was
washed with brine (200 mL), dried with MgSO4, and concentrated
in vacuo. Purification of the crude product by flash column
chromatography (pure toluene to toluene/EtOAc, 5:1) afforded an
inseparable mixture of 10 and 11 (2.0 g, 92%) as a slightly yellow
oil. The mixture was used for the next step without further purifica-
tion.
1462, 1386, 1360, 1248, 1220, 1097, 1031, 882, 834, 774, 669,
657 cm–1.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and copies of the 1H NMR and 13C
NMR spectra of all compounds.
Acknowledgments
R. F. is a recipient of a DOC-fFORTE-fellowship of the Austrian
Academy of Sciences at the Department of Organic Chemistry,
University of Vienna. The Austrian Science Fund (FWF) (Fonds
zur Förderung der wissenschaftlichen Forschung) is gratefully
acknowledged for financial support (Project FWF-P20697-N19).
The authors thank Dr. Hanspeter Kählig (University of Vienna)
for assistance with NMR spectroscopy.
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Received: October 28, 2013
Published Online: January 8, 2014
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