Synthesis of (±)-oleocanthal via a tandem intramolecular Michael cyclization-HWE olefination

Article abstract of DOI:10.1016/j.tetlet.2009.03.145

A synthesis of racemic oleocanthal has been accomplished in 11 steps from 1,3 propanediol by a key tandem intramolecular Michael cyclization-Horner-Wadsworth-Emmons olefination.

Full text of DOI:10.1016/j.tetlet.2009.03.145

Tetrahedron Letters 50 (2009) 2713–2715
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Tetrahedron Letters
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Synthesis of ( )-oleocanthal via a tandem intramolecular Michael
cyclization–HWE olefination
Brandon J. English a, Robert M. Williams a,b,
*
a Department of Chemistry, Colorado State University, 1301 Center Avenue, Fort Collins, CO 80523, USA
b University of Colorado Cancer Center, Aurora, CO 80045, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthesis of racemic oleocanthal has been accomplished in 11 steps from 1,3 propanediol by a key tan-
dem intramolecular Michael cyclization–Horner–Wadsworth–Emmons olefination.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 10 February 2009
Revised 9 March 2009
Accepted 10 March 2009
Available online 25 March 2009
The secoiridoids are a class of plant-derived monoterpenes
containing the substituted pyran core of secologanin (1). This class
of natural products arises in biological systems from the oxidative
cleavage of the loganin skeleton (2) by the cytochrome P450
enzyme secologanin synthase (Fig. 1).1 Secologanin then under-
goes various modifications to produce a wide array of structures
displaying diverse biological activities including analgesic2, anti-
inflammatory3, anti-arthritic4, anti-allergenic5, antibacterial6, and
antiviral7 activities. Coupling of the simple secoiridoids with trypt-
amine gives rise to a large class (>250 examples) of indole and
oxindole alkaloids including geissoschizine, strychnine, reserpene,
ajmaline, and the Vinca alkaloids with highly varied carbon frame-
works and biological profiles.
We reasoned that, given the structural similarities of the seco-
loganin-derived natural products, synthetic access to the more
complex secoiridoid and secologanin tryptamine alkaloids could
be obtained through a single strategically functionalized interme-
diate. As a test case for our strategy, our attention focused on the
secoiridoid oleocanthal (3) for both its relative structural simplicity
that retains the compact arrangement of functionality of the seco-
iridoids and its demonstrated potency as an inhibitor of the COX-1
and COX-2 enzymes3,8, making it an ideal entry point into the syn-
thesis of this class of natural products. Important to our retrosyn-
thetic analysis was proceeding through an intermediate with
functionalities that could be independently manipulated allowing
for future adaptation of this synthesis to produce a diverse selec-
tion of natural product targets. Lactone 5 appeared ideal for this
purpose as it contained the requisite carbon backbone as well as
properly situated synthetic handles with orthogonal reactivities.
We envisioned the dialdehyde moietyof 3 arisingfrom the reduc-
tion and oxidation of lactone 5 whose carbon framework could be
assembled through a key tandem Michael cyclization and Horner–
Wadsworth–Emmons (HWE) olefination9 of phosphonoacetic ester
6 (Scheme 1). This allows for the simultaneous assembly of the
desired lactone core, the addition of the two-carbon olefin sidechain,
and the introduction of a stereogenic center. Studies to control the
absolute configuration of this new stereogenic center through the
introduction of chiral auxiliaries are currently underway.
O
OGlu
Me
O
Me
O
OH
OH
HO2C
O
O
O
O
MeO2C
CO2Me
secologanin (1)
oleocanthal (
3)
HO
elenolic acid
secologanin
synthase
O
O
OGlu
N
CO2Me
O
Me
OH
H
OH
N
H
H
OHC
MeO2C
O
CO2Me
Me
oleuropein aglycone
loganin (2)
geissoschizine
Figure 1. Structures of several secologanin derivatives.
O
O
O
O
Me
O
Me
O
OH
O
OTIPS
O
O
O
oleocanthal (
4
3)
O
O
O
O
P(OMe)2
P(OMe)2
HO
HO
Me
O
CO2Me
CO2Me
5
6
CO2Me
* Corresponding author. Tel.: +1 970 491 6747; fax: +1 970 491 3944.
E-mail address: rmw@lamar.colostate.edu (R.M. Williams).
Scheme 1. Retrosynthetic analysis.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.145

2714
B. J. English, R. M. Williams / Tetrahedron Letters 50 (2009) 2713–2715
O
O
hex./EtOAc to yield 28.56 g (96%) of the title compound as a color-
MeO2C
less oil. 1H NMR (300 MHz, CDCl3): d 6.96 (dt, J = 15.6, 7.2 Hz, 1H),
5.87 (dt, J = 15.9, 1.5 Hz, 1H), 3.71 (s, 3H), 3.70 (m, 2H), 2.40 (qd,
J = 6.6, 1.8 Hz, 2H), 0.87 (s, 9H), 0.04 (s, 6H); 13CNMR (75 MHz,
CDCl3): d 167.1, 146.4, 122.7, 61.7, 51.6, 35.9, 26.0, 18.5, À5.2; IR
(NaCl, film): 1729, 1660 cmÀ1; HRMS (+TOF): [M+H]+ 245.1568
calcd for C12H25O3Si, found: 245.1571; Rf = 0.40 (9:1 hex./EtOAc).
Synthesis of phosphonate 6: To a 1 L HDPE bottle was added
24.85 g (101.7 mmol, 1 equiv) (E)-methyl 5-(tert-butyldimethylsi-
lyloxy)pent-2-enoate (8) dissolved in 500 mL dry THF followed
by 53 mL HF as a 48% solution in H2O. The reaction was stirred
MeO2C P(OMe)2
1. HF, THF, 90%
LiCl, iPr2NEt
MeCN
96%
2.
HO2C P(O)(OMe)2
OTBS
OTBS
DCC, CH2Cl2
>99%
7
8
O
O
O
Cs2CO3, MeCN, 40oC
P(OMe)2
O
Me
O
then MeCHO
42%
CO2Me
6
5
CO2Me
Scheme 2. Synthesis of lactone 5.
for 6 h at ambient temperature, then slowly added to NaHCO3(satd)
,
and extracted twice with EtOAc. Combined organic layers were
dried over Na2SO4 and concentrated. The resulting residue was dis-
solved in 1:1 hex./EtOAc and filtered through a short silica gel plug.
Concentration yielded 11.90 g (90%) of the desired alcohol as a pale
yellow oil.
Assembly of lactone 5 began with the synthesis of aldehyde 7
from 1,3-propanediol utilizing the method reported by Schaus
and coworkers.10 Reaction of 7 with commercially available tri-
methyl acetophosphonate under Masamune-Roush conditions pro-
duced the unsaturated ester 8 as a single isomer and in good yield
(Scheme 2). Deprotection and subsequent esterification gave the
desired substrate 6, which upon treatment with Cs2CO3 and acetal-
dehyde in warm acetonitrile underwent sequential intramolecular
Michael cyclization and HWE olefination to yield lactone 5 as an
inconsequential 1.6:1 mixture of E/Z isomers.
Selective hydrolysis of the methyl ester of 5 yielded acid 9 that
was esterified with protected tyrosol 10 affording lactone 11,
which upon reduction and Dess–Martin oxidation gave the dialde-
hyde precursor to oleocanthal as a single isomer (Scheme 3). This
sensitive dialdehyde rapidly decomposed when treated with stan-
dard deprotection conditions (HF, HF-pyr, and TBAF) but under-
went clean deprotection to furnish ( )-oleocanthal when the
neutral conditions described in the literature by Smith et al. were
employed (HF, TBAF aqueous THF at pH 7).2
We have demonstrated a short and scalable synthesis of
( )-oleocanthal, which can be readily adapted to allow access to
a diverse selection of secoiridoid natural products. Current efforts
are underway both to control the absolute stereochemistry of the
key intramolecular Michael cyclization step of this approach and
then to employ this method to synthesize several secoiridoids
and secologanin tryptamine alkaloids.
Synthesis of ester 8: To a flame dried 2 L round-bottomed flask
(RBF) charged with 20.98 mL (121.3 mmol, 1.1 equiv) methyl 2-
(dimethoxyphosphoryl)acetate dissolved in 1000 mL dry MeCN
were added 6.170 g (145.5 mmol, 1.2 equiv) LiCl and then
21.12 mL (121.3 mmol, 1.2 equiv) iPr2NEt. The reaction was stirred
at ambient temperature for 15 min and then 22.84 g (121.3 mmol,
1 equiv) aldehyde 7 dissolved in a minimum of MeCN was added.
After stirring for 4 h the reaction was concentrated to approxi-
mately 50% volume, added to brine, and extracted thrice with
EtOAc. Combined organic layers were dried over Na2SO4, concen-
trated, and purified by silica gel chromatography eluting with 4:1
An oven-dried 100 mL RBF was charged with 2.940 g
(22.58 mmol, 1 equiv) of the above alcohol, 4.560 g (27.11 mmol,
1.2 equiv) 2-(dimethoxyphosphoryl)acetic acid, and 45 mL dry
CH2Cl2. To this was added 5.590 g (27.11 mmol, 1.2 equiv) DCC dis-
solved in a minimum volume of CH2Cl2. The reaction was stirred
for 45 min at ambient temperature before being filtered through
a Celite pad and concentrated. Purification by flash chromatogra-
phy eluting with EtOAc yielded 6.310 g (>99%) of 6 as a colorless
solid. 1H NMR (300 MHz, CDCl3): d 6.84 (dt, J = 15.6, 6.9 Hz, 1H),
5.83 (dt, J = 15.9, 1.5 Hz, 1H), 4.18 (t, J = 6.3 Hz, 2H), 3.74 (s, 3H),
3.70 (s, 3H), 3.65 (s, 3H), 2.91 (d, JHP = 21.6 Hz, 2H), 2.49 (qd,
J = 6.6, 1.5 Hz, 2H); 13CNMR (75 MHz, CDCl3) d 166.6, 165.7,
144.1, 123.5, 63.6, 53.4, 51.7, 34.3, 32.5, 31.4; IR (NaCl, film):
1724, 1660; HRMS (+TOF) calcd for C10H18O7P [M+H]+ 281.0785,
found 281.0788; Rf = 0.18 (EtOAc).
Synthesis of lactone 5: To 179 mg (0.639 mmol, 1 equiv) (E)-
methyl 5-(2-(diethoxyphosphoryl)acetoxy)pent-2-enoate (6) dis-
solved in 3 mL dry MeCN in an oven-dried 25 mL RBF was added
416 mg (1.28 mmol, 2 equiv) Cs2CO3. The reaction was heated to
reflux for 1.5 h, cooled to 0 °C, and 107 lL (1.92 mmol, 3 equiv)
freshly distilled acetaldehyde was added in a single portion. The
reaction was vigorously stirred for 16 h at ambient temperature
and was then acidified with 1 N HCl. This mixture was extracted
thrice with EtOAc. Combined organic layers were dried over
Na2SO4, concentrated, and purified by silica gel flash chromatogra-
phy eluting with 2:1 to 1:1 hex./EtOAc to yield 53.0 mg (42%) of 5
(1.6:1 E/Z) as a yellow oil.
Synthesis of lactone 11: To 69.0 mg (0.345 mmol, 1 equiv) crude
lactone 5 dissolved in 2 mL 3:1 THF:H2O in a 10 mL RBF was added
25.0 mg (1.03 mmol, 3 equiv) LiOH. The reaction was stirred at
ambient temperature for 2 h and then acidified with 1 N HCl. This
mixture was extracted thrice with EtOAc, dried over Na2SO4, and
concentrated. The resulting residue was purified by silica gel flash
chromatography eluting with 1:1:0.01 to 0:1:0 hex./EtOAc/HOAc
to yield 44.0 mg (70%) of the desired acid as an inseparable mixture
(1.6:1 E/Z) of E/Z isomers as a pale yellow oil.
To 36.0 mg (0.193 mmol, 1 equiv) of the above acid dissolved in
2 mL dry CH2Cl2 in an oven-dried 10 mL RBF and cooled to 0 °C was
added 85.0 mg (0.290 mmol, 1.5 equiv) 2-(4-(triisopropylsilyl-
oxy)phenyl)ethanol (10) followed by 60.0 mg (0.290 mmol,
1.5 equiv) DCC and a spatula tip of DMAP. The reaction was stirred
for 16 h at ambient temperature, filtered through Celite, concen-
trated, and purified by silica gel flash chromatography eluting with
2:1 hex./EtOAc to yield 89.0 mg (>99%) of the title compound as a
colorless oil. 1H NMR (300 MHz, CDCl3): Z-isomer d 7.05 (m, 2H),
6.82 (m, 2H), 6.19 (qd, J = 7.2, 1.5 Hz, 1H), 4.26 (t, J = 6.9 Hz, 2H),
4.11 (td, J = 9.0, 3.6 Hz, 1H), 3.81 (m, 1H), 3.09 (m, 1H), 2.84 (dt,
J = 17.1, 6.9 Hz, 3H), 2.44 (ddd, J = 15.6, 8.9, 6.3 Hz, 2H), 2.04 (dd,
J = 7.2, 1.2 Hz, 3H), 1.24 (m, 3H), 1.10 (s, 18H), E-isomer d
OTIPS
O
HO
Me
10
LiOH
H2O, THF
70%
O
5
DCC, DMAP
CH2Cl2
9
CO2H
>99%
O
O
O
O
1. DIBAl-H, THF
2. DMP, CH2Cl2
O
O
Me
O
55% 2 steps
OH
Me
3. HF, TBAF
THF, pH ~7.0
O
80%
11
oleocanthal (3)
OTIPS
Scheme 3. Synthesis of ( )-oleocanthal.

B. J. English, R. M. Williams / Tetrahedron Letters 50 (2009) 2713–2715
2715
7.01–7.09 (m, 3H), 6.79 (m, 2H), 4.24–4.38 (m, 3H), 4.16 (m, 1H)
3.32 (m, 1H), 2.85 (t, J = 7.2 Hz, 2H), 2.41 (m, 2H), 1.83 (d,
J = 7.5 Hz, 3H), 1.70 (m, 2H), 1.22 (m, 3H), 1.07 (m, 18H); 13CNMR
(75 MHz, CDCl3) mixture of isomers d 172.4, 171.4, 166.5, 154.9,
142.1, 139.6, 133.8, 130.2, 129.9, 129.8, 120.1, 120.1, 68.2, 65.5,
38.0, 34.4, 34.1, 29.6, 27.4, 27.0, 25.8, 25.2, 18.3, 14.4, 12.8; IR
(NaCl, film) 1732, 1511 cmÀ1; HRMS (+TOF) calcd for C26H41O5Si
[M+H]+ 461.2728, found 461.2722; Rf = 0.24 (2:1 hex./EtOAc).
Synthesis of oleocanthal (3): To 47.0 mg (0.102 mmol, 1 equiv)
(S)-4-(triisopropylsilyloxy)phenethyl 2-(3-ethylidene-2-oxotetra-
hydro-2H-pyran-4-yl)acetate (11) dissolved in 1 mL dry THF in a
3.7 mg (80%) of ( )-oleocanthal as a colorless film. All spectral
properties matched data reported in the literature.8
Acknowledgments
We gratefully acknowledge financial support from the National
Institutes of Health (Grant GM068011). Mass spectra were ob-
tained on instruments supported by the National Institutes of
Health Shared Instrumentation Grant No. GM49631. We also grate-
fully acknowledge an Eli Lilly Graduate Fellowship to B.J.E. from Eli
Lilly.
10 mL flame-dried RBF at À78 °C was slowly added 102
1 M solution of DIBAL in toluene. After stirring the reaction for
L dry MeOH was added, the reaction was al-
lowed to warm to ambient temperature, and 5 mL saturated Ro-
chelle’s salt solution was added. After stirring for 30 min this
mixture was extracted thrice with EtOAc, dried over Na2SO4, con-
centrated, and purified by silica gel flash chromatography eluting
with 4:1 hex./EtOAc to yield 48 mg of the desired alcohol as a col-
orless oil.
This residue was dissolved in 1 mL dry CH2Cl2, charged to a
10 mL oven-dried RBF, and cooled to 0 °C. To this solution was
added 65.0 mg (0.153 mmol, 1.5 equiv) Dess–Martin periodinane
and the reaction was stirred for 3 h at ambient temperature be-
fore the addition of 5 mL 5:1 Na2S2O3(satd):NaHCO3(satd) solution.
This mixture was stirred for 15 min before being extracted thrice
with CH2Cl2. Combined organic layers were dried over Na2SO4
and concentrated. Flash chromatography eluting with 4:1 hex./
EtOAc yielded 26.0 mg (55%) of the desired dialdehyde as a color-
less oil.
lL of a
References and notes
1 h at À78 °C 100
l
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To 7.0 mg of the above dialdehyde dissolved in 250
lL dry THF
8. Smith, A. B., III; Han, Q.; Breslin, P. A. S.; Beauchamp, G. K. Org. Lett. 2005, 7,
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at 0 °C was added 50 L of a solution prepared by the addition of
l
40% HF(aq) to a 1 M THF solution of TBAF until the pH of the result-
ing solution reached 7 as evidenced by pH paper. The reaction was
stirred for 2 h at 0 °C, added to brine, and extracted thrice with
EtOAc. Combined organic layers were dried over Na2SO4, concen-
trated, and taken up in 1:2 hex./EtOAc. This solution was filtered
through a short plug of silica gel and concentrated to yield
9. For applications of similar tandem Michael cyclization-HWE olefinations see:
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Whitwood, A. C.; Taylor, R. J. K. Eu. J. Org. Chem. 2008, 28, 4769–4783; Edwards,
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10. Sha, L.; Westbrook, J. A.; Schaus, S. E. J. Am. Chem. Soc. 2004, 126(37), 11440–
11441.