Synthesis of the C6-C14 Fragment of Euphosalicin

Article abstract of DOI:10.1055/s-0034-1380422

The synthesis of the C6-C14 fragment of euphosalicin, a highly oxygenated modified jatrophane diterpene, is described. Key steps in the preparation of this versatile intermediate are an Ireland-Claisen rearrangement and a Shibasaki direct asymmetric aldol reaction.

Full text of DOI:10.1055/s-0034-1380422

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 1852–1856
letter
1852
U. Rinner et al.
Letter
Synlett
Synthesis of the C6–C14 Fragment of Euphosalicin
Christian Aichinger
direct catalytic
asymmetric aldol
pinacol coupling
O
Johann Mulzer
Uwe Rinner*1
OTBS
MOMO
OPMB
SnBu3
6
AcO
14
14
Institute of Organic Chemistry, University of Vienna,
Währinger Straße 38, 1090 Wien, Austria
uwe.rinner@jku.at
PMBO
C6–C14 fragment
Ireland–Claisen
rearrangement
O
NicO
AcO
OAc
ONic
H
AcO
6
OTBS
MOMO
2
AcO
lithiation/
addition
TBSO
O
5
OPMB
H
euphosalicin
TESO
O
western fragment
(previously reported)
Received: 09.04.2015
Accepted after revision: 07.05.2015
Published online: 19.06.2015
O
AcO
H
18
DOI: 10.1055/s-0034-1380422; Art ID: st-2015-b0256-l
18
NicO
Abstract The synthesis of the C6–C14 fragment of euphosalicin, a
highly oxygenated modified jatrophane diterpene, is described. Key
steps in the preparation of this versatile intermediate are an Ireland–
Claisen rearrangement and a Shibasaki direct asymmetric aldol reac-
tion.
OAc
AcO
AcO
ONic
AcO
euphosalicin (1)
jatrophane skeleton
12-membered ring
13-membered ring
Key words natural products, total synthesis, aldol reaction, rear-
Figure 1 Formal incorporation of the jatrophane C18 methyl group
rangement, hydrostannation
gives the euphosalicin skeleton
Plants of the genus Euphorbia have been common ingre-
dients in herbal folk medicine for thousands of years, and
members of this highly diverse plant family have been used
for the treatment of a variety of medical conditions.2 In the
last century, phytochemists became interested in active in-
gredients and numerous biologically active natural prod-
ucts, among them the tiglianes, daphnanes, and the
jatrophanes were isolated.3 Despite their fascinating struc-
tural and biological properties only few synthetic studies
toward jatrophane diterpenes have been published.4
In 2001, the highly oxygenated diterpene euphosalicin
(1) was isolated from Euphorbia salicifolia by Hohmann and
co-workers.5 Although it has a unique [11.3.0] bicyclic
structure, it is closely related to the jatrophanes: formal in-
corporation of the jatrophane C18 methyl group into the
macrocycle gives the euphosalicin skeleton as shown in Fig-
ure 1.
jor reason for cancer chemotherapy to fail.8 Thus, blocking
P-glycoprotein is a promising approach to increasing the ef-
ficacy of existing anticancer drugs.
The intriguing structure – the dense functionalization
and uncommon framework – in combination with the
promising biological properties prompted us to search for a
synthetic route toward euphosalicin (1). A few years ago,
we reported a concise route to the cyclopentane fragment
of the title compound.4k,l Herein, we describe the prepara-
tion of the requisite C6–C14 fragment of euphosalicin.
The retrosynthetic analysis is outlined in Scheme 1. We
intended to employ a derivative of a previously prepared
cyclopentane fragment, namely five-membered-ring syn-
thon 24k,l which should be connected to the C6–C14 frag-
ment 6 of euphosalicin (1) under lithiation conditions or by
means of a Nozaki–Hiyama–Kishi (NHK) reaction. The 13-
membered macrocycle should then be elaborated using a
pinacol coupling reaction. The key intermediate in the
preparation of fragment 6 was Weinreb amide 7, which we
envisaged to construct through an Ireland–Claisen rear-
rangement9 of 8. This would ensure the E configuration of
the internal alkene, allow us to easily set the quaternary
C10 stereocenter, as well as derive both stereogenic centers
From a biological point of view, 1 is a potent inhibitor of
P-glycoprotein,6 an adenosine triphosphate-dependent
transporter responsible for the efflux of druglike molecules
from cells.7 Many types of cancer lines overexpress this
transporter, leading to multidrug resistance, which is a ma-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1852–1856

1853
U. Rinner et al.
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pinacol coupling
HO
OTBS
OH
OTBS
MOMO
2
HO
2
O
O
OTBS
AcO
5
14
H
O
TESO
2
18
O
4
5
NicO
2
3
O
6
H
AcO
OAc
AcO
O
ONic
AcO
OTBS
MOMO
OPMB
OTBS
O
TBSO
O
lithiation/addition
or NHK reaction
1
18
SnBu3
OPMB
10
14
NMe
OMe
6
PMBO
PMBO
8
6
7
Scheme 1 Retrosynthetic analysis of euphosalicin
in 7 from the same source of chirality. Compound 8 should
be accessible through Evans aldol chemistry or from Roche
ester 9 via a short synthetic sequence.
The synthesis of the C6–C14 fragment of euphosalicin
started with the preparation of monoprotected diol 14, as
outlined in Scheme 2. Silylation of (R)-Roche ester (9) and
subsequent exposure to N,O-dimethylhydroxylamine and
trimethyl aluminum furnished Weinreb amide 10, which
was reacted with vinyl lithium. The newly formed vinyl ke-
tone 11 was then reduced in the presence of the chiral Co-
rey–Bakshi–Shibata (CBS) oxazaborolidine and monopro-
tected diol 14 was obtained in excellent yield and good dia-
stereoselectivity (dr >12:1).
1. TBSCl, Et3N
2. MeNHOMe,
Al(Me)3
OH
O
vinyl-
lithium
TBSO
O
TBSO
O
OMe
NMe
OMe
75%
60%
(2 steps)
9
10
11
(S)-CBS,
Me2S•BH3
85%
dr > 12:1
Bu2BOTf,
i-Pr2NEt;
acrolein
1. LiBH4
2. TBSCl,
Et3N
O
O
O
O
N
OH
TBSO
OH
O
N
O
An alternative route toward 14 proceeded via an Evans
aldol reaction10 of 12 to give 13, followed by reductive re-
moval of the auxiliary. Selective mono-TBS protection and
esterification11 of the remaining free hydroxyl group with
PMB-protected lactic acid 1912 yielded building block 8.
With two reliable routes to monosilylated diol 8 at
hand, we proceeded to develop conditions for the crucial
[3,3]-sigmatropic rearrangement. The controlled genera-
tion of the C10 stereocenter in the envisaged Ireland–
Claisen reaction relied on the selective formation of the de-
sired enolate geometry as well as on the rearrangement
transition-state geometry favoring the desired product. In
the rearrangement of 8, the first prerequisite should be sat-
isfied by the α-oxygenation on the ester, which Kallmerten
showed to strongly favor (Z)-silyl enol ethers, presumably
due to chelation effects (15).13 The second requirement
should be ensured by the preferentially equatorial position-
ing of the R group in the rearrangement transition state 16.
When 8 was subjected to LDA followed by TMSCl at
–78 °C and left to warm to room temperature, clean rear-
rangement to 17 was observed. However, analysis of the re-
sulting material revealed a diastereomeric ratio of only 3:1.
Separation of this mixture by HPLC was not possible, likely
because of the marginal interaction between the remote
stereocenters. Acid 17 was reacted with a number of chiral
alcohols, but the resulting esters did not allow the separa-
tion of the diastereomers either. Other reaction conditions
63%
(2 steps)
68%
Ph
Ph
12
13
14
19, DIC,
DMAP
71%
M
OPMB
a) LDA, THF, –78 °C
O
O
or
b) KHMDS, toluene,
–78 °C
TBSO
O
TBSO
O
OPMB
quant. (a and b)
15
8
a) dr 3:1
b) only 17
TMSCl
‡
Me
O
COOH
OPMB
TBSO
R
PMBO
17
TMSO
16, R =
OTBS
MeNHOMe⋅HCl,
DIC, DMAP, Et3N
56%
OTBS
OPMB
O
1. NaH, PMBCl
2. LiOH, H2O
OH
NMe
OMe
COOEt
18
COOH
85%
(2 steps)
PMBO
19
7
Scheme 2 Preparation of Weinreb amide 7
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1852–1856

1854
U. Rinner et al.
Letter
Synlett
were screened with the hope of increasing the diastereo-
meric ratio to a synthetically viable point. Different sol-
vents, enolization temperatures, or lithium bases did not
give significantly better results. Inspired by a 1999 report
from Langlois,14 we investigated the use of KHMDS as base.
Fortunately, desired acid 17 was obtained as single isomer
when 8 was treated with KHMDS followed by TMSCl and
warmed to –20 °C.15 Without further purification, Weinreb
amide 7 was obtained upon exposure of acid 17 to N,O-di-
methylhydroxylamine hydrochloride, N,N′-diisopropylcar-
bodiimide (DIC) and base.
Our initial strategy toward the C6–C14 fragment of eu-
phosalicin envisaged the formation of methyl ketone 20
from Weinreb amide 7 (Scheme 3) and the utilization of
this compound in aldol reactions with either acrolein (24)
or bromoacrolein (25). Thus, 7 was reacted with methyl
magnesium bromide which delivered methyl ketone 20 in
good yield. However, despite numerous attempts, aldol re-
actions of 20 with 24 or 25 failed to give the desired prod-
ucts. Under basic conditions, complete deprotonation of the
methyl ketone was proven by D2O quench, but the generat-
ed enolate did not add to aldehydes even at elevated tem-
peratures. Lewis acidic conditions led to rapid decomposi-
tion. We reasoned that Reformatsky conditions might be
better suited to access the desired fragment, and thioether
21 was prepared via addition of PhSCH2Li to Weinreb amide
7.16 Unfortunately, all attempts to generate 22 or 23 from
thioether 21 were also met with failure.
cleanly furnished aldehyde 26. Brown allylation18 then de-
livered homoallyl alcohol 27 in excellent yield but low ste-
reoselectivity. Other allylation protocols, for example utiliz-
ing the Duthaler–Hafner catalyst,19 resulted in improved
product ratios, but the yields were generally lower.
OTBS
O
OTBS
O
DIBAL–H
84%
NMe
OMe
H
PMBO
PMBO
B(Ipc)2
7
26
31
85% brsm
dr 2.4:1
31
1. MOMCl,
DIPEA
2. PdCl2,
CuCl, O2
OTBS
OH
OTBS
MOMO
O
9
73%
(2 steps)
PMBO
PMBO
28
27
1. LHMDS, TMSCl, –78 °C
2. KOt-Bu, CHBr3, –20 °C to r.t.
OTBS
MOMO
O
OTBS
MOMO
OTMS
Br
PMBO
PMBO
Br
Br
29
30
Scheme 4 Rearrangement route to bromoenone 30
The diastereomers could easily be separated by means
of flash column chromatography. The stereochemical as-
signment of the newly installed hydroxyl moiety at C9 in 27
was accomplished by means of detailed NOE studies of the
corresponding cyclic PMP acetal, obtained by oxidation of
the PMB ether in 27 (cyclic intermediate not shown; for a
similar strategy see the oxidation of epi-32, Scheme 6). Sub-
sequent protection of the desired major product as MOM
ether was followed by Wacker oxidation20 of the terminal
double bond. Methyl ketone 28, the precursor for the key
cyclopropanation reaction, was isolated in excellent yield.
While enolization and silylation could be cleanly effected,
exposure of the resulting alkene to dibromocarbene sources
led to the isolation of starting material or to decomposition.
As all attempts to isolate bromoenone 30 were met with
failure, we started searching for a more predictable route.
We turned our attention to the aldol reactions of alde-
hyde 26. As the reaction of 26 with either methyl vinyl ke-
tone or the corresponding brominated derivative failed to
deliver the desired products in acceptable yield (reactions
not shown), the approach depicted in Scheme 5 emerged as
the most promising route to fragment 6. Aldehyde 26 was
treated with Shibasaki’s (S)-LLB catalyst21 (34) and buty-
none 35 to give 32 as a mixture of diastereomers with 76%
yield and a diastereomeric ratio of 1.6:1. The quaternary
stereocenter at C10 and the presence of an oxygen func-
tionality in α-position of the acceptor in this key Shibasaki
direct aldol reaction (26) could be responsible for the un-
OTBS
O
OTBS
O
MeMgBr
NMe
OMe
66%
(81% brsm)
PMBO
PMBO
20
7
O
X
H
PhSMe, BuLi
DABCO
aldol
conditions
base or Lewis
acid; 24 or 25
81%
24 X = H
25 X = Br
OTBS
O
Reformatsky OTBS
conditions
O
OH
X
24 or 25
PMBO
21
PMBO
SPh
22 X = H
23 X = Br
Scheme 3 Aldol approach toward fragments 22 or 23
An interesting sequence for the elaboration of α-bromo-
α,β-unsaturated ketone motifs was reported by Ohshiro
several years ago.17 The route featured the cyclopropana-
tion of a silyl enol ether. The subsequent rearrangement
with loss of one halide and opening of the cyclopropane
ring delivered the desired halogenated enone. We wished
to evaluate this method and prepared methyl ketone 28 as
synthon for this transformation (Scheme 4). The route com-
menced with DIBAL-H reduction of Weinreb amide 7 which
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1852–1856

1855
U. Rinner et al.
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OTBS
OH
O
OTBS
MOMO
OH
OTBS
O
1. MOMBr, DIPEA
34, 35
2. 36, i-PrOH
–45 °C to –30 °C
10
10
(R)
H
76%
dr 1.6:1
55% brsm
(2 steps)
PMBO
PMBO
PMBO
26
TMS
TMS
32
33
1. K2CO3, MeOH
2. PMBCl, NaH
3. Pd(PPh3)4,
Bu3SnH
38%
(3 steps)
Li
O
O
O
O
O
La
Li
Ru
O
Li
OTBS
MOMO
OPMB
HN
Ph
NTs
Ph
O
SnBu3
TMS
35
PMBO
6
34
Scheme 5 Final steps to the C16–C14 fragment of euphosalicin
36
usually low level of stereoselectivity. We reasoned that the
oxygen at C10 might take part in the formation of compet-
ing chelated intermediates, resulting in the observed de-
creased stereoinduction.
Next, the secondary alcohol in 32 was protected as
ether using MOMBr (lower yield was observed when MOM-
Cl was used). Purification was again performed at low tem-
peratures due to stability concerns. The following transfer
hydrogenation using Noyori’s catalyst23 (36) smoothly pro-
duced 33 in good yield without any trace of the undesired
epimer.24 The resulting product was stable on silica gel, al-
lowing for easier purification.
Chromatographic purification proved difficult, as 32
readily decomposed on silica. However, the problem could
be solved by performing flash chromatography at –25 °C.22
The relative stereochemistry of the minor isomer epi-32
was determined by oxidation of the PMB ether to the cyclic
PMP acetal. A mixture of two cyclic products 37 and 38 was
obtained, differing in the stereochemistry of the acetal po-
sition. Analysis of NOE correlations (Scheme 6) confirmed
the desired stereochemical configuration in the major aldol
product 32.
The sequence continued with a K2CO3/MeOH-mediated
TMS cleavage25 and PMB protection of the propargylic alco-
hol. At this stage, we examined several methods of hydro-
metalating or hydrohalogenating the alkyne. The typically
harsh conditions of acidic or radical hydrohalogenations
seemed unsuitable for our substrate. Trost’s ruthenium-cat-
alyzed hydrosilylation26 proceeded with great regioselec-
tivity in moderate yields, but we were unable to elaborate
the resulting vinyl silane into a viable synthetic handle. In
our hands, Hoveyda’s nickel-based hydroalumination,27
while delivering excellent results for several substrates, did
not work for alkynes with oxygenation in the propargylic
position. Finally, we resorted to transition-metal-catalyzed
OTBS
OH
O
(S)
PMBO
TMS
epi-32
83%
dr 1.3:1
DDQ, MS
hydrostannylations. Pd(PPh3)4, Pd(PPh3)2Cl2,28 and Rh-
TMS
TMS
29
OTBS
OTBS
Cl(CO)(PPh3)2
all gave broadly similar results, with
Pd(PPh3)4 generally giving the best yields and selectivities.
In all cases we observed reduction of the alkyne to the dou-
ble bond as side reaction. The desired hydrostannylated
material 6 was formed along with minor amounts of reduc-
tion product and of a linear product with the tributyltin
moiety at the terminal position. The three-component mix-
ture was easily separable on silica gel, allowing the isola-
tion of the desired coupling precursor 6 in acceptable yield.
Summarizing, our route provides access to the desired
C6–C14 fragment of euphosalicin in reliable 13 steps and in
quantities sufficient for the completion of the synthesis of
the natural product. With 6 in hand, future efforts are di-
O
H
O
H
H
O
O
H
+
O
O
37
38
NOE
interactions
OMe
OMe
Scheme 6 NOE correlations in cyclic PMP acetals 37 and 38
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 1852–1856

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U. Rinner et al.
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rected toward the elaboration of suitable coupling protocols
with the previously synthesized five-membered-ring syn-
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We thank the Austrian Science Fund (FWF) for financial support
(FWF-R45-N19 and FWF-P20697-N19).
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380422.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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