Towards the total synthesis of Pl-3: Preparation of the eastern fragment through a diastereoselective SmI2-mediated reformatsky reaction

Article abstract of DOI:10.1002/ejoc.201300148

The jatrophane diterpene Pl-3, isolated in 2003 from Euphorbia platyphyllos, is a structurally complex natural product with highly promising biological properties that include pronounced antiproliferative activity and the inhibition of the efflux-pump activity of multidrug resistance p-glycoprotein. Herein, the synthesis of the eastern fragment of Pl-3 is outlined. The target compound is synthesized in nine synthetic operations in good overall yield, starting from readily available D-ribose. The key step in the preparation of the eastern part of Pl-3 is a diastereoselective SmI₂-mediated Reformatsky reaction. The proposed route is highly flexible and could also be applied to the synthesis of structurally related jatrophane diterpenes.

Full text of DOI:10.1002/ejoc.201300148

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300148
Towards the Total Synthesis of Pl-3: Preparation of the Eastern Fragment
through a Diastereoselective SmI2-Mediated Reformatsky Reaction
Rita Fürst,[a] Christoph Lentsch,[a] and Uwe Rinner*[a]
Keywords: Natural products / Terpenoids / Samarium / Diastereoselectivity / Multidrug resistance
The jatrophane diterpene Pl-3, isolated in 2003 from Euphor-
bia platyphyllos, is a structurally complex natural product
with highly promising biological properties that include pro-
nounced antiproliferative activity and the inhibition of the
efflux-pump activity of multidrug resistance p-glycoprotein.
Herein, the synthesis of the eastern fragment of Pl-3 is out-
lined. The target compound is synthesized in nine synthetic
operations in good overall yield, starting from readily avail-
able -ribose. The key step in the preparation of the eastern
part of Pl-3 is a diastereoselective SmI2-mediated Reformat-
sky reaction. The proposed route is highly flexible and could
also be applied to the synthesis of structurally related jatro-
phane diterpenes.
D
ration of Euphorbia diterpenes is also of medicinal impor-
tance.
Introduction
The genus Euphorbia, a member of the Euphorbiaceae
plant family, is one of the largest genera among flowering
plants comprising more than 2000 species. Euphorbia
plants, also known as spurges, are endemic in tropical and
subtropical regions as well as in temperate climate zones.
Several members are in cultivation and are of great eco-
nomic importance. For example, the Pará rubber tree
(Hevea brasiliensis) serves as a source of natural rubber,
whereas Cassava (Manihot esculenta) is an important an-
nual crop that is rich in carbohydrates. Other members,
such as poinsettia (Euphorbia pulcherrima), are cultivated
for their appealing nature.
Because of their pronounced biological activities, spurges
have been common ingredients in traditional herbal folk
medicine, and they are mainly used in the treatment of can-
cerous conditions, swellings, and warts.[1] The milky sap (la-
tex) is a common attribute of members of the Euphor-
biaceae plant family. It contains a large number of structur-
ally diverse diterpenes, which are responsible for the appli-
cation of spurges in traditional phytotherapy.[2] Several of
these diterpenes were also identified as highly active inhibi-
tors of the adenosine-5Ј-triphosphate (ATP)-dependent ef-
flux pump p-glycoprotein, which is responsible for multi-
drug resistance in cancer.[3] Given that resistance to preva-
lent drugs is one of the major drawbacks in the develop-
ment of cancer therapeutics, progress in the synthetic prepa-
Chemical interest in the biologically active ingredients of
the genus Euphorbia started with the isolation of jatrophone
by Kupchan in 1970.[4] Since then, numerous diterpenes of
the jatrophane, tigliane, ingenane, and lathyrane frame-
works have been isolated and, to some extent, evaluated for
their biological activity.[2] Despite their challenging struc-
tural features, only few synthetic efforts towards these fasci-
nating natural products have been reported to date.[5]
Pl-3 (1) was isolated by Hohmann and co-workers from
Euphorbia platyphyllos in 2003.[6] As outlined in Figure 1,
jatrophane diterpenes are characterized by a highly func-
tionalized trans-bicyclo[10.3.0]pentadecane framework. In-
dividual diterpenes often only differ in the stereochemical
pattern of the methyl and hydroxy groups, whereas the sub-
stitution pattern remains highly similar.
[a] Department of Organic Chemistry, University of Vienna,
Währinger Straße 38, 1090 Vienna, Austria
E-mail: uwe.rinner@univie.ac.at
Homepage: http://rinner-group.univie.ac.at
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300148.
Re-use of this article is permitted in accordance with the Terms
and Conditions set out at http://onlinelibrary.wiley.com/journal/
10.1002/(ISSN)1099-0690/homepage/2046_onlineopen.html
Figure 1. Jatrophane skeleton and representative jatrophane diter-
penes.
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R. Fürst, C. Lentsch, U. Rinner
SHORT COMMUNICATION
The retrosynthetic analysis is shown in Scheme 1. The periodate cleavage of the formed diol afforded unsaturated
final operation in the synthesis of Pl-3 is a metathesis reac- aldehyde 12 in excellent yield.[8]
tion to close the macrocyclic ring, whereas advanced inter-
With 12 in hand, the crucial diastereoselective Reformat-
mediate 4 should become available from cyclopentane 5 and sky reaction could be attempted. According to literature
alkene 6 through cross-metathesis. The key step in the prep- precedents, the S configuration at the newly generated
aration of the eastern part of Pl-3 is a diastereoselective stereocenter is expected when bromoacyl oxazolidinone 7,
SmI2-mediated Reformatsky reaction.[7] In an attempt to readily available on multigram scale upon acylation of ox-
take advantage of the chiral pool, d-ribose was identified azolidinone 15 and 2-bromoisobutyryl bromide (16), is al-
as an ideal starting material to access alkene 6. The utiliza- lowed to react with aldehyde 12.[7a,9] Unfortunately, as
tion of different sugars and the application of an enantio- shown in Table 1, initial attempts with the use of tin[9,10]
meric chiral auxiliary in the Reformatsky reaction should and zinc[11] for the generation of the nucleophile in the Re-
furthermore allow the facile preparation of related frag- formatsky reaction resulted in reisolation of the starting
ments for the synthesis of other jatrophane diterpenes.
material. The desired product, although only in low yield,
was first obtained when chromium salts were employed
(Table 1, entries 3–6).[12] Cp2TiCl (Cp = cyclopentadienyl)
has been described to promote Reformatsky reactions,[13]
but we chose to utilize SmI2 next and were able to isolate
oxazolidinone 13 in excellent yield as a single diastereomer
(the opposite diastereomer was not observed by NMR spec-
troscopy), which was further converted into methoxymethyl
(MOM)-protected intermediate 14. The high level of selec-
tivity can be explained by the exclusive formation of a
pentacoordinate transition state, as described by Thornton
and Pridgen.[7a,14] Steric repulsion of the auxiliary and pre-
sumably the bulky geminal dimethyl group efficiently pre-
vents Re attack and forces the system to undergo the de-
sired Si attack. The S-configured hydroxy group in 13
(Scheme 3) is formed through exclusive stereochemical con-
trol of the chiral auxiliary.
Scheme 1. Retrosynthetic analysis.
Recently, we reported the synthesis of the cyclopentane
moiety of Pl-3 (1).[5h] Herein, we will discuss the prepara-
tion of the eastern fragment (i.e., 6).
Table 1. Reaction conditions in the diastereoselective Reformatsky
reaction.
Entry
Metal and solvents
Temp. [°C]
% Yield of 13
1
2
3
4
5
6
7
SnCl2, LiAlH4, THF
Zn, THF
CrCl2, LiI, THF
CrCl2, THF
CrCl2, NiCl2, THF
CrCl3, LiAlH4, THF
SmI2, THF
0 to r.t.
0 to r.t.
r.t.
r.t.
r.t.
r.t.
–78
0
0
7
23
Results and Discussion
The first approach towards alkene 6 started with aceton-
ide protection of d-ribose (9) as outlined in Scheme 2. Ini-
tially, we intended to install the alkene moiety required for
the cross-metathesis reaction by Tebbe olefination of the
corresponding methyl ketone, which should be accessible
from terminal alkene 14 after Wacker oxidation. Thus, acet-
onide 10 was allowed to react with Wittig salt 11 before
Ͻ10[a]
Ͻ10[a]
85
[a] Yield was determined by analysis of the crude product by 1H
NMR spectroscopy.
Scheme 2. Preparation of alkene 14 (DIPEA = N,N-diisopropyl-
ethylamine).
Scheme 3. Transition-state model for the diastereoselective Re-
formatsky reaction.
2
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Towards the Total Synthesis of Pl-3
Scheme 4. Determination of the stereochemistry.
The proposed configuration of the newly installed hy- THF with tBuOK as the base, α-racemization occurred and
droxy moiety in 13 was unambiguously confirmed by com- a diastereomeric mixture of 27/28 in a 5:1 ratio was isolated
parison of the coupling constants between H-4 and H-3 in in moderate 34% yield. When toluene was used as the sol-
cyclic intermediates 18 and 20, according to the Karplus vent, the exclusive formation of desired alkene 27 was ob-
correlation and NOESY experiments (Scheme 4). Cleavage served; however, the isolated yield did not exceed 30%. Sev-
of the terminal double bond in 13 and 19, available upon eral other protocols were investigated: potassium hexa-
Reformatsky reaction of 12 with ent-7, by ozonolysis was methyldisilazane (KHMDS) in THF afforded exclusively
followed by pyridinium chlorochromate (PCC) oxidation of undesired diastereomer 28 (Table 2, entry 7), whereas other
the resulting lactol. Whereas the H-4–H-3 coupling con- bases such as NaH and BuLi resulted in reisolation of the
stant in 20, which originated from the alcohol with the R starting material. As the yield in the methylenation reaction
configuration, was 1.0 Hz, a value of 3.7 Hz was measured could not be further improved, another approach was elab-
for cyclic intermediate 18, and thus, the stereochemical con- orated.
figuration of alcohol 13 could be confirmed.
All attempts to convert alkene 14 into methyl ketone 22
through Wacker oxidation failed and only resulted in reiso-
lation of the starting material. As outlined in Scheme 5, di-
hydroxylation of the terminal double bond with OsO4 and
periodate cleavage of the resulting diol allowed the isolation
of highly unstable aldehyde 21. However, the conversion of
21 into methyl ketone 22 proved to be troublesome, as ad-
dition of the methyl Grignard reagent and subsequent
oxidation of the secondary alcohol delivered the desired
compound in low and irreproducible yield.
Scheme 6. Second approach – preparation of alkenes 27 and 28
(TBS = tert-butyldimethylsilyl).
Table 2. Methylenation of lactol 26.
Scheme 5. Preparation of methyl ketone 22 (NMO = N-methyl-
morpholine-N-oxide; DMP = Dess–Martin periodinane).
Entry
Reagent/solvent
Temp.
[°C]
Time
[h]
% Yield
(27/28)
In a modified approach, we intended to install the methyl
ketone at an early stage to circumvent the problems dis-
cussed above. As shown in Scheme 6, the route started with
Lewis acid promoted conversion of d-ribonolactone (23)
into acetonide 24. Silylation of the primary hydroxy group
delivered lactone 25, which was treated with methyllithium
to afford lactol 26 as a masked methyl ketone in quantita-
tive yield as a single diastereomer.[15] Next, we intended to
install the terminal double bond. Methylenation of 26 with
Tebbe’s reagent was unsuccessful, and even at elevated tem-
perature no conversion could be detected (Table 2, entries 1
and 2). Surprisingly, when allowed to react with the methyl
1
2
3
4
5
6
7
8
Tebbe reagent/THF
0
3
3
4
12
12
12
14
4
0
0
Tebbe reagent/THF r.t. to 80
tBuOK/THF[a]
NaH/DMSO[b]
NaH/THF[c]
0 to r.t.
r.t. to 50
–20 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
34 (5:1)
0
0
0
nBuLi/THF[d]
KHMDS/THF[a]
tBuOK/toluene[a]
13 (Ͻ1:99)
30 (Ͼ99:1)
[a] The Wittig salt was deprotonated at 0 °C over 20 min and at r.t.
over 1.5 h before 26 was added. [b] NaH was heated in DMSO to
75 °C for 45 min before the Wittig salt was added at 0 °C, and
deprotonation was accomplished at r.t. over 20 min. [c] The Wittig
salt was deprotonated at r.t. over 2 h. [d] The Wittig salt was depro-
Wittig reagent (11) under standard reaction conditions in tonated at –78 °C over 1 h.
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R. Fürst, C. Lentsch, U. Rinner
SHORT COMMUNICATION
In our third approach, protection of d-ribonolactone
(23) as its acetonide was followed by exposure of the lac-
tone to pyrrolidine at elevated temperature to obtain amide
29 in excellent yield (Scheme 7). Next, silylation of both
hydroxy functionalities was followed by addition of meth-
yllithium to deliver the corresponding methyl ketone, which
could be smoothly converted into alkene 31 upon reaction
with Tebbe’s reagent. Removal of both silyl ethers and sub-
Experimental Section
Preparation of 33: To a solution of SmI2 (0.1 m in THF, 100 mL,
10 mmol, 2.5 equiv.) in a 250 mL round bottom Schlenk flask was
added a solution of bromide 7 (1.44 g, 4.41 mmol, 1.1 equiv.) and
aldehyde 32 (683 mg, 4.01 mmol, 1.0 equiv.) in degassed THF
(60 mL, 3 pump–freeze–thaw cycles) at –78 °C by cannula. The re-
action mixture was stirred for 1 h at –78 °C before it was quenched
by the addition of aqueous saturated solutions of sodium thio-
sequent oxidative cleavage of the vicinal diol with NaIO4 sulfate (50 mL) and sodium hydrogen carbonate (50 mL) at –78 °C,
and the biphasic system was warmed to room temperature. The
two phases were separated, and the aqueous layer was extracted
with ethyl acetate (3ϫ). The combined organic extract was dried
with sodium sulfate and filtered, and the organic solvents were re-
moved under reduced pressure to deliver alcohol 33 as a light-
yellow oil, which was further purified by flash column chromatog-
raphy (hexanes/ethyl acetate, 9:1) to provide 33 (1.14 g, 68%).
delivered aldehyde 32, the precursor for the crucial dia-
stereoselective Reformatsky reaction. Again, as discussed
for the first approach, the desired secondary alcohol was
obtained in good yield as a single isomer when a degassed,
precooled THF solution of bromide 7 and aldehyde 32 was
added to a SmI2 solution at –78 °C. Final MOM protection
delivered advanced intermediate 34 and completed the
preparation of the eastern part of Pl-3 (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 described in this communication.
Acknowledgments
R. F. is a recipient of a DOC-fFORTE fellowship of the Austrian
Academy of Sciences at the Institute of Organic Chemistry, Univer-
sity of Vienna. The Fonds zur Förderung der wissenschaftlichen
Forschung (FWF) is gratefully acknowledged for financial support
of this work (project number FWF-P20697-N19).
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Conclusions
We have established a general nine-step sequence for the
synthesis of the eastern fragment of Pl-3. The Reformatsky
reaction, described in detail within this manuscript, can be
employed in the synthesis of jatrophane diterpenes to estab-
lish recurring structural motifs within the eastern part. The
application of different carbohydrate derivatives as the
starting material in combination with the highly diastereo-
selective SmI2-mediated Reformatsky reaction grants access
to a variety of structurally related Euphorbiaceae di-
terpenes. Owing to the diastereoselective control of the chi-
ral auxiliary within the SmI2-mediated Reformatsky reac-
tion, the utilization of this reaction will be of interest for
other synthetic applications. The scope of the synthetic
route and the completion of the preparation of Pl-3 are cur-
rently under investigation in our group.
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4
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Towards the Total Synthesis of Pl-3
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Received: January 28, 2013
Published Online: ᭿
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R. Fürst, C. Lentsch, U. Rinner
SHORT COMMUNICATION
Total Synthesis
R. Fürst, C. Lentsch, U. Rinner* ...... 1–6
Towards the Total Synthesis of Pl-3: Prepa-
ration of the Eastern Fragment through a
Diastereoselective SmI2-Mediated Re-
formatsky Reaction
An efficient and flexible nine-step pro-
cedure for the preparation of the eastern
fragment of the jatrophane diterpene Pl-3
is developed. The sequence starts with
available starting material from the chiral
pool and features a highly diastereoselec-
tive SmI2-mediated Reformatsky reaction
as the key step.
Keywords: Natural products / Terpenoids /
Samarium / Diastereoselectivity / Multi-
drug resistance
d-ribose as
a
cheap and readily
6
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