A concise synthesis of rooperol and related 1,5-diarylpent-1-en-4-ynes

Article abstract of DOI:10.1016/j.tetlet.2013.10.138

Two powerful strategies: rapid construction of allylic alkynoates via cyclopropenium ion chemistry and mild, palladium-catalyzed decarboxylative coupling were employed in a concise, 5-steps synthesis of the natural product rooperol. The overall approach a

Full text of DOI:10.1016/j.tetlet.2013.10.138

Tetrahedron Letters 55 (2014) 137–141
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A concise synthesis of rooperol and related
1,5-diarylpent-1-en-4-ynes
a
Sean M. Kerwin a,b, , Jonathan Cha
⇑
a Department of Chemistry, University of Texas at Austin, Austin, TX 78712, USA
b Division of Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Two powerful strategies: rapid construction of allylic alkynoates via cyclopropenium ion chemistry and
mild, palladium-catalyzed decarboxylative coupling were employed in a concise, 5-steps synthesis of the
natural product rooperol. The overall approach allows the preparation of rooperol analogs in as few as 3
steps.
Received 5 October 2013
Revised 22 October 2013
Accepted 28 October 2013
Available online 6 November 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropenium
Palladium-catalyst
Decarboxylative coupling
Catechol
Desilylation
Norlignans
Extracts of the corm of the African potato (Hypoxis hemerocalli-
dea) are widely used in South Africa for a variety of medical
conditions.1 Investigation of the biologically active constituents
of H. hemerocallidea have led to the isolation and structural
elucidation of the major phenolic constituent of this plant, the
bis-glucoside hypoxoside (1) (Fig. 1).2 The hypoxoside and its
aglycone, rooperol (2) were the first natural products reported to
possess the unusual 1,5-diarylpent-1-en-4-yne moiety. However,
more recently a number of other plant-derived polyphenolic
natural products have been reported that possess either this core
structure3 or the related 1,5-diarylpent-4-yne-1,2-diol moiety.4–6
These natural products are particularly interesting, as they are
all derived from plants that have been used medicinally. For exam-
ple, rooperol has been reported to possess anticancer, anti-inflam-
matory, antibacterial, and antioxidant activities.7–10 Interestingly,
we recently demonstrated that rooperol inhibits the mitogen-
activated protein kinase p38 through a unique mechanism that
a
may account for the anti-inflammatory effects of this natural
product.11
Despite the promising biological activity of rooperol and related
1,5-diaryl-pent-1-en-4-ynes, only one total synthesis has been
reported. Drewes and co-workers prepared rooperol via a low-
yielding coupling of a terminal acetylene with an allylic bromide.12
The challenge with this coupling, and the subsequent low-yielding
deprotection step, was attributed to the propensity of the
1-en-4-yne moiety to undergo base-catalyzed isomerization.
In our continuing studies of the p38a kinase inhibition by roop-
erol and analogs, we set out to develop a more concise and efficient
route to this class of natural products. Our goal was to establish a
more robust route by avoiding the basic conditions during the con-
struction and deprotection of the 1,5-diaryl-pent-1-en-4-yne sys-
tem. Here we report a much improved route to rooperol and
analogs that employs two powerful strategies: a rapid construction
of allylic alkynoates via cyclopropenium ion chemistry (A- > B,
Scheme 1) and a mild palladium-catalyzed decarboxylative sp–sp3
coupling of these allylic alkynoates to afford the 1,5-diaryl-
pent-1-en-4-yne system (B- > C, Scheme 1). These, together with
an improved procedure for deprotection of catechol silylethers,
enable a high-yielding, 5-steps synthesis of rooperol and the
preparation of rooperol analogs in as few as three steps.
Figure 1. Structure of the 1,5-diarylpent-1-en-4-yne natural product hypoxoside
and its aglycone rooperol.
Detty and co-workers have described an interesting approach to
phenylpropiolate esters via phenyl-substituted trichlorocycloprop-
enes 4 (Scheme 2).13 These are formed by Friedel–Crafts alkylation
⇑
Corresponding author.
E-mail address: skerwin@austin.utexas.edu (S.M. Kerwin).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.10.138

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S. M. Kerwin, J. Cha / Tetrahedron Letters 55 (2014) 137–141
Scheme 1. Retrosynthetic analysis of rooperol and analogs.
Scheme 2. Cyclopropenium route to arylpropiolate esters.13
of electron-rich aromatic compounds by the trichlorocyclopropeni-
um species derived from tetrachlorocyclopropene (3). Alcoholysis
of cyclopropenes 4 proceeds through proposed intermediate dialk-
oxycyclopropenes 5, which undergo ring-opening to afford ortho-
esters 6. These can be isolated, or more conveniently hydrolyzed
via work-up to provide the esters 7 (Scheme 2).
Although not widely adopted, the approach shown in Scheme 2
has potential advantages to alternative routes to phenylpropiolate
esters. In the present case, we sought bis(tert-butyldimethylsilyl)-
right,16–20 this strategy for their rapid construction could have
even broader applications than that described here for the synthe-
sis of rooperol and analogs.
In a single synthetic transformation, tetrachlorocyclopropene in
the presence of AlCl3 was allowed to react with bis(TBDMS)-pro-
tected catechol at À78 °C. Following a rapid aqueous work-up,
the crude aryltrichlorocyclopropene was treated with excess meth-
anol and NaHCO3. After acidic workup and chromatography, the
methyl alkynoate 7a was isolated in moderate yield (Scheme 3).
However, attempts to hydrolyze 7a under aqueous acidic or basic
conditions met with failure due to the lability of the catechol silyl
ethers (see above). In contrast, when the same procedure was car-
ried out with allyl alcohol in place of methanol, the allyl ester 7b
was obtained (Scheme 3).21 Deallylation of 7b under conditions re-
ported by Sato and co-workers to limit subsequent decarboxyl-
ation of the carboxylic acid (morpholine in the presence of
catalytic Pd2dba3/1,3-diphenylphosphopropane)22 afforded the
carboxylic acid 7c in good yield. The requisite allylic alkynoate
7d was prepared by standard esterification of the acid 7c with
the functionalized cinnamyl alcohol 8,23 prepared in two steps
from caffeic acid.
protected catechol-functionalized phenyl-propiolic esters
B
(Scheme 1). Although tert-butyldimethylsilylethers (TBDMS
ethers) are generally considered resistant to deprotection under
basic conditions, TBDMS ethers of phenols14 and catechols15 un-
dergo deprotection even under relatively mild basic hydrolytic
conditions. This lability limited our initial attempts to prepare
TBDMS-protected catechol-functionalized phenylpropiolic acid
precursors of B (see Scheme 3 and discussion, below). Thus, we
reasoned that the use of allyl alcohols in the alcoholysis of 4
(Scheme 2), although not reported in the original work, might pro-
vide an alternative route to these esters. Use of allyl alcohol should
afford allyl phenylpropiolates 7 (R = allyl, Scheme 2) suitable for
mild palladium-catalyzed deprotection to the corresponding acids.
Alternatively, the required cinnamyl esters B (Scheme 1) might be
directly obtained from the arylcyclopropenes A by employing cin-
namyl alcohols in the alcoholysis. Since allyl and cinnamyl phenyl-
propiolates are versatile synthetic intermediates in their own
A more concise preparation of 7d was attempted by repeating
the arylcyclopropene alcoholysis by employing the alcohol 8 in
place of allyl alcohol (Scheme 4). This failed to afford 7d; instead
the ether 9 was obtained along with more polar, uncharacterized
material. Since the alcoholysis is carried out in the presence of
Scheme 3. Synthesis of functionalized phenylpropiolate esters.

S. M. Kerwin, J. Cha / Tetrahedron Letters 55 (2014) 137–141
139
Scheme 4. Attempted preparation of 7d directly from 3 affords instead the ether 9, possibly via an alternative attack (blue arrows) on a cyclopropenone ketal intermediate.
cinnamyl sp3 carbons, as opposed to attack at the ketal carbon to
afford the orthoester precursor to 7d.
In contrast to the case of 8 (Scheme 4), use of cinnamyl alcohol or
3,4-difluorocinnamyl alcohol in the alcoholysis step directly affords
the desired esters 7e and
f from tetrachlorocyclopropene
(Scheme 5). In these cases, small amounts of the ethers analogous
to 9 are observed in the 1H NMR spectra of the crude reaction mix-
tures. Interestingly, the product 7e derived from cinnamyl alcohol
containing a small amount of 3-phenylpropanol (ca. 5%) was en-
riched in the 3-phenylpropanol ester (ca. 10–15%). This enrichment
may be due to a process analogous to that shown in Scheme 4, in
which the cinnamyl groups of an intermediate ketal are preferen-
tially attacked as compared to the alkyl groups derived from the
saturated alcohol. This would lead to enrichment of the saturated
groups in the resulting orthoesters, and thus the final ester product.
Next, a mild and base-free palladium-catalyzed decarboxylative
coupling recently reported by Tunge and co-workers24 was em-
ployed to construct the pent-1-en-4-yne system. Palladium-
catalyzed decarboxylative coupling of esters 7d–f proceeded in
the presence of 5 mol % of Pd[P(Ph)3]4 in THF at 80 °C to give
Scheme 5. Direct synthesis of cinnamyl phenylpropiolate esters.
excess base, it is unlikely that 9 forms via simple acid-catalyzed
etherification of 8. Rather, 9 may be derived from a cyclopropenone
ketal intermediate (Scheme 4) via an attack by 8 on one of the
Scheme 6. Palladium-catalyzed decarboxylative coupling and subsequent deprotection.

140
S. M. Kerwin, J. Cha / Tetrahedron Letters 55 (2014) 137–141
i) AlCl3, CH2Cl2, rt
OTBDMS
, -78 °C
ii)
TBDMSO
O
iii) Aqueous work-up
iv) allyl alcohol, NaHCO3, rt
55 %
OTBDMS
OR
Cl
Cl
Cl
Cl
OTBDMS
R = Allyl
16
17
18
Pd2dba3
(Ph)2P(CH2)3P(Ph)2
morpholine
THF, rt
88 %
R = H
TBDMSO
OH
8
TBDMSO
EDC, DMAP, CH2Cl2, rt
46 %
R = CH2
OTBDMS
OTBDMS
Pd[P(Ph)3]4
toluene
80 °C
45 %
OR
OR
OR
OR
KF
19
R = TBDMS
HBr/AcOH
DMF
0 °C
20 R = H
71 %
Scheme 7. Synthesis of a rooperol hydroquinone analog.
protected rooperol 10d12 and analogs 10e and f in good yield.25
We attempted the desilylation of these protected catechols by
treatment with TBAF in THF at À78 °C, but in accord with previous
work,12 this afforded mostly polymeric material. However, a
recently reported improved procedure for the deprotection of
particularly labile silylated polyphenols was much more effec-
tive.26 Thus, treatment of 10d–f in DMF with KF and HBr/AcOH
afforded rooperol (2), 3,4-bis(dehydroxy)rooperol 11e,27 and the
difluororooperol analog 11f in good yield (Scheme 6).
In order to probe the generality of this approach, we also pre-
pared the A-ring hydroquinone analog of rooperol (Scheme 7).
Addition of the bis(tert-butyldimethylsilyl)-protected hydroqui-
none to the cyclopropenium species formed from tetrachlorocyclo-
propene and aluminum chloride in dichloromethane, followed by
rapid aqueous work-up and alcoholysis with excess allyl alcohol
afforded the allyl ester 16. Palladium-catalyzed deallylation and
subsequent coupling with the functionalized cinnamyl alcohol 8
gave the ester 19, which underwent smooth palladium-catalyzed
decarboxylative coupling to afford the protected pent-1-en-4-yne
19. Deprotection of 19 employing the same conditions as above
produced the hydroquinone rooperol analog 20.
approach to allyl arylpropiolates, which undergo palladium-cata-
lyzed deallylation (in the presence of base) or decarboxylative cou-
pling (under neutral conditions). This same approach also afforded
the rooperol hydroquinone analog 20. In some cases, this general
approach allows an even more concise route to rooperol analogs;
analogs 11e and f were prepared in just 3 steps. Thus, the approach
we report here has the potential to greatly facilitate the biological
study of rooperol and analogs. Moreover, the direct preparation of
allyl and cinnamyl arylpropiolates employed here is noteworthy,
as these are versatile synthetic intermediates. Biochemical and
biological evaluation of these analogs is currently under
investigation.
Acknowledgements
The technical assistance of Ashley Jewett and Nakul Shah is
gratefully acknowledged. This work was supported by grants to
S.M.K. from the Robert Welch Foundation (F-1298) and the Texas
Institute for Drug and Diagnostic Development (TI3D).
Supplementary data
In conclusion, a concise synthesis of rooperol in 5 steps and 17%
overall yield from tetrachlorocyclopropene was accomplished. This
is an improvement from the previously published route that re-
quired 9 total steps and proceeded in 4.1% overall yield from ethyl
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.10.
138.
caffeate.12 This improved route employs
a cyclopropenium

S. M. Kerwin, J. Cha / Tetrahedron Letters 55 (2014) 137–141
ice/acetone bath.
141
A
solution of 843 mg (2.49 mmol) of 1,2-bis((tert-
References and notes
butyldimethyl-silyl)oxy)benzene in 3 mL of CH2Cl2 was added dropwise, and
then the ice bath was removed. After the reaction mixture had warmed to
room temperature, it was placed in a 50 °C oil bath until the evolution of HCl
subsided (ca. 10 min). After cooling on ice, the reaction mixture was treated
with 10 mL of ice cold water. This was extracted 2Â with CH2Cl2 and the
combined organic layers dried over MgSO4 and filtered into a flask containing
856 mg (14.7 mmol) of allyl alcohol. After the addition of 2.55 g NaHCO3, the
mixture was stirred at room temperature for 30 min. The reaction mixture was
filtered, warmed in a 50 °C oil bath for ca. 5 min, and then 15 mL of 1 N HCl was
added. The layers were separated and the organic layer was washed once with
dilute NaHCO3 and dried over Na2SO4. The residue upon filtration and
evaporation of the solvent was subjected to flash chromatography (0, 2.5%
EtOAc/Hexane) to afford 7b as a slightly yellow oil (627 mg, 1.40 mmol, 66%).
1H NMR (400 MHz, CDCl3) d 7.10 (1H, dd, J = 8.3, 2.0 Hz), 7.04 (1H, d, J = 2.0 Hz),
6.79 (1H, d, J = 8.3 Hz), 5.97 (1H, ddt, HJ = 17.2, 10.4, 5.9 Hz), 5.40 (1H, dm,
J = 17.2 Hz), 5.30 (1H, dm, J = 10.4 Hz), 4.72 (2H, dm, J = 5.9 Hz), 0.98 (9H, s),
0.97 (9H, s), 0.21 (6H, s), 0.20 (6H, s). 13C NMR (100 MHz, CDCl3) d 154.0, 150.3,
146.9, 131.3, 127.5, 125.5, 121.1, 119.3, 111.9, 87.5, 79.5, 66.4, 25.8 (2C),18.5,
18.4, À4.1, À4.2. IR (thin film): 3020, 2954, 2931, 2869, 2860, 2213, 1704,
1508 cmÀ1. HRMS (ESI+) calcd for C24H38NaO4Si2 (M+Na)+ 469.2201, found
469.2196.
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21. General Procedure: A mixture of 290 mg (2.17 mmol) AlCl3 and 5 mL CH2Cl2 was
stirred at room temperature under argon while 376 mg (2.1 mmol) of
tetrachlorocyclopropene was added dropwise. The resulting suspension was
stirred at room temperature for an additional 15 min and then cooled in a dry
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25. General Procedure: A solution of 134 mg (0.171 mmol) of ester 7d in 2.5 ml of
freshly-distilled THF was transferred under argon to a reaction tube containing
10 mg (0.0086 mmol) of Pd[P(Ph)3]4 and the tube was sealed. After heating for
4 h in a 80 °C oil bath, the contents of the tube were transferred to a round-
bottomed flask with EtOAc, the solvent evaporated and the residue was
subjected to flash chromatography (0–1% EtOAc/hexanes) to afford 10d as a
yellow oil (105 mg, 0.142 mmol, 83%). 1H NMR and IR matched that previously
reported.12 13C NMR (100 MHz, CDCl3) d 147.3, 146.8, 146.6, 146.4, 130.9,
125.3, 124.3, 122.4, 121.0, 120.9, 119.6, 118.9, 116.5, 105.0, 85.2, 82.4, 26.0,
25.9, 22.9, 18.5, 18.4, À4.1. HRMS (ESI+) calc for C41H71O4Si4 (MH)+ 739.4424,
found 739.4422.
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