Microwave-Assisted Claisen Rearrangement: Synthesis of Naturally Occurring TRAIL-Resistance-Overcoming Tyrosine Derivative

Article abstract of DOI:10.1080/00397911.2014.974614

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a tumor necrosis factor (TNF) family ligand that binds on the death receptors, DR4 and DR5, activating apoptotic pathways selectively in cancer cells and thus has become a promising cancer therapeutic agent. Compound 1, isolated from Streptomyces sp. IFM 10937, has shown activity in overcoming TRAIL resistance in AGS cells. Synthesis of 1 has been accomplished from L-tyrosine in an overall high-yielding reaction sequence. GRAPHICAL ABSTRACT.

Full text of DOI:10.1080/00397911.2014.974614

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Synthetic Communications: An International Journal
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Microwave Assisted Claisen Rearrangement: Synthesis
of Naturally Occurring Trail-Resistance-overcoming
Tyrosine Derivative
M. Manshaa, Y. Abbasa & N. Ullaha
a Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran, Saudi
Arabia
Accepted author version posted online: 03 Nov 2014.
To cite this article: M. Mansha, Y. Abbas & N. Ullah (2014): Microwave Assisted Claisen Rearrangement: Synthesis of Naturally
Occurring Trail-Resistance-overcoming Tyrosine Derivative, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2014.974614
To link to this article: http://dx.doi.org/10.1080/00397911.2014.974614
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MICROWAVE ASSISTED CLAISEN REARRANGEMENT: SYNTHESIS OF
NATURALLY OCCURRING TRAIL-RESISTANCE-OVERCOMING
TYROSINE DERIVATIVE
M. Mansha, Y. Abbas, N. Ullah
1Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran,
Saudi Arabia
Corresponding author N. Ullah Chemistry Department, King Fahd University of
Petroleum and Minerals, Dhahran 31261, Saudi Arabia E-mail: nullah@kfupm.edu.sa
Abstract
TRAIL is a TNF family ligand that binds on the death receptors, DR4 and DR5,
activating apoptotic pathways selectively in cancer cells and thus has become a promising
cancer therapeutic agent. Compound 1, isolated from Streptomyces sp. IFM 10937, has
shown activity in overcoming TRAIL resistance in AGS cells. Synthesis of 1 has been
accomplished from L-tyrosine in an overall high yielding reaction sequence.
KEYWORDS: Cancer; TRAIL; tyrosine derivative, total synthesis, olefin cross-
metathesis reaction
INTRODUCTION
1

Cancers are genetic diseases that results from the deregulation of cell growth and cell
death pathways due to genomic alterations. Apoptosis, the process of programmed cell
death, is a genetically programmed biochemical process that removes unwanted cells and
maintains tissue homeostasis. Tumor necrosis factor-related apoptosis inducing ligand
(TRAIL), a tumor necrosis factor (TNF) family member,[1,2] activates apoptotic pathways
selectively in cancer cells[3] through binding on the death receptors, DR4[4,5] and DR5[6,7]
After initiation by the death-receptor pathway, TRAIL-induced apoptosis results in
activation of effector caspase-3, death-inducing signaling complex (DISC) formation and
proteolytic activation of caspase-8.[8] TRAIL has emerged as an attractive antineoplastic
agent due to its remarkable ability to selectively kill tumoral cells while leaving normal
cells unscathed.[9] Unlike the other members of the TNF superfamily, in vivo
administration of TRAIL has been proved to be safe.[10] However, in the case of highly
malignant tumors, a reasonable numbers of cancer cells have intrinsic or acquired
resistance to TRAIL-induced apoptosis.[11] Therefore, discovery of compounds that can
abrogate TRAIL resistance has attracted a great deal of attention in anticancer drug
discovery.
.
In a recent study, bioassay-guided fractionation of Streptomyces sp. IFM 10937, has led
to the isolation of anew tyrosine derivative 1 (Figure 1).[12] Compound 1 was evaluated
for their activity in overcoming TRAIL resistance in AGS (human gastric
adenocarcinoma) cells. Combined treatment of 75 or 150 μM 1 and 100 ng/mL TRAIL
with AGS cell lines reduced cell viability to 77 ± 7% and 67 ± 5% of control levels (p <
0.01), respectively, which suggested a possible synergism between the two agents.
2

In our ongoing efforts towards the total synthesis bioactive natural products,[13-16] we now
wish to disclose the synthesis of 1.
DISCUSSION
Synthesis of the desired compound 1 was envisaged from the olefin cross-metathesis
reaction of intermediate 4, which in turn, was to be synthesized from Claisen
rearrangement of intermediate 3. Thus, L-tyrosine 2 was converted to intermediate 3 by
the operations of esterification, N-boc protection and O-allylation based on literature
known procedures[17] (Scheme 1).
However, Claisen rearrangement of intermediate 3 either under thermal or microwave
irradiation conditions at different temperatures, using N,N-dimethylaniline or DMF as
solvents were unsuccessful. For instance, under thermal conditions reaction in N,N-
dimethylaniline or DMF at reflux resulted the starting material intact whereas heating
neat 3 at elevated temperatures led to the decomposition of 3, with no desired product
formation. Likewise, under microwave conditions, reaction at lower temperature (200 oC,
250 W, 1 h) in DMF resulted unchanged 3 whereas heating the reaction at higher
temperature (250 oC, 250 W, 45 minutes) in N,N-dimethylaniline led to the deprotection
of N-Boc group. Deprotection of N-Boc group under microwave conditions using mild
base or under thermolytic conditions are well known.[18] To address the N-deprotection
problem we moved on to make the N-acetyl derivative 5 which in turn was synthesized
from intermediate 2 according to a literature known procedure[19] (Scheme 1). Claisen
3

rearrangement of intermediate 5 in N,N-dimethylaniline under microwave irradiation at
250 oC gave the desired rearranged phenol 6 in excellent yield (75%). Acetylation of
intermediate 6 under standard conditions rendered 7 in a very high yield. Olefin cross-
metathesis reaction between intermediate 7 and 2-methyl-2-butene, using second-
generation Grubbs catalyst yielded the desired 8 in excellent yield (84%). It is noteworthy
that O-prenylation of O-deallylated 5 followed by Claisen rearrangement would possibly
have given access to the O-deacetylated 8. However, such O-prenylation would have
required palladium catalysed reaction between deallylated 5 with commercially not
available isobutyl-2-methyl-3-butene-2-ylcarbonate.[20] O-prenylation of tyrosines in
proteins have recently been accomplished with prenyltransferase LynF, an enzyme from
TruF family.[21,22] Finally, exposure of intermediate 8 under basic condition at room
temperature ultimately produced the desired 1 in 43% overall yield from 5 (Scheme 1).
All the spectral data of 1 matched with those of the previously isolated material.[12]
EXPERIMENTAL
Elemental analysis was carried out on a Perkin Elmer Elemental Analyzer Series 11
Model 2400 (PerkinElmer Inc. USA). IR spectra were recorded on a Thermo Scientific
Nicolet 6700 FT-IR Perkin Elmer 16F PC FTIR spectrophotometer (Thermo Scientific
USA). 1H and 13C NMR spectra were measured in CDCl3 and CD3OD using TMS as
internal standard on a JEOL JNM-LA 500 MHz spectrometer (JEOL USA Inc.).
Analytical TLC was carried out on silica gel 60 F254 plates (E. Merck); column
chromatography was carried out on silica gel (200-400 mesh, E. Merck).
4

(S)-Methyl 2-acetamido-3-(3-allyl-4-hydroxyphenyl)propanoate (6, C15H19NO4): To a
microwave reaction vessel containing a solution of aryl ether 5 (0.75 g, 2.70 mmol) in
N,N-dimethylaniline (4 ml). After gentle bubbling nitrogen through the solution for 1
min, the vessel was placed inside CEM Discover S-Class microwave synthesizer where it
was exposed to microwaves at 250 oC (260 W) for 2 h. After completion of the reaction,
the mixture was diluted with ethyl acetate (50 mL) and extracted with 3M hydrochloric
acid (3 x 10 mL). The organic layer was washed successively with saturated sodium
hydrogen carbonate (15 mL) and then brine (10 mL), dried over anhydrous sodium
sulfate, filtered and concentrated under vacuum. Column chromatography purifications of
the yellow oily material, eluting with ethyl acetate:hexane (1:1) yielded compound 6 as a
pale yellow solid. Yield: 0.56 g, 75%; mp 91-92 oC; [α]D25 +25.95 (c. 1.15, CHCl3); IR
(neat): 3418, 3300, 3081, 3006, 2956, 1717, 1662, 1510, 1432, 1209, 1121 cm-1; 1H NMR
(CDCl3, 500 MHz): δ 1.92 (s, 3H, NCOCH3), 2.96 (dd, 2H), 3.27 (m, 2H), 3.66 (s, 3H,
OCH3), 4.76 (m, 1H), 4.99-5.03 (m, 2H), 5.90 (m, 1H), 5.99 (d, 1H, J = 7.9 Hz, NH),
6.62 (m, 1H, aromatics), 6.72 (m, 2H, aromatics); 13C NMR (CDCl3, 500 MHz): δ 23.05,
34.46, 37.05, 52.35, 53.31, 115.64, 116.07, 125.92, 127.26, 128.13, 131.04, 136.46,
153.39, 170.05, 172.29. Anal. calcd. for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found:
C, 64.93; H, 6.94; N, 5.01.
(S)-Methyl 2-acetamido-3-(4-acetoxy-3-allylphenyl)propanoate (7, C17H21NO5): To a
solution of compound 6 (0.5 g, 1.80 mmol) in anhydrous dichloromethane (15 mL) at 0
oC was added triethylamine (0.75 ml, 5.41 mmol). After bring stirred for 10 minutes,
acetic anhydride (0.35 ml, 3.60 mmol) was added dropwise and the reaction was stirred
5

for 2 h at room temperature. The mixture was added ethyl acetate (30 mL) and washed
successively with saturated sodium hydrogen carbonate (15 mL) and brine (10 mL). The
organic layer was dried over anhydrous sodium sulfate and evaporated under vacuum to
obtain compound 7 as an off-white solid. Yield: 0.57 g, 99%; mp 104 oC; [α]D25 +56.6 (c.
1.0, CHCl3); IR (neat): 3311, 3086, 2948, 1740, 1649, 1639, 1543, 1497, 1433, 1371,
1202, 1185, 1166 cm-1; 1H NMR (CDCl3, 500 MHz): δ 1.99 (s, 3H, NCOCH3), 2.29 (s,
3H, COCH3), 3.10 (t, 2H, J = 5.5 Hz), 3.25 (d, 2H, J = 6.7 Hz), 3.72 (s, 3H, OCH3), 4.86
(m, 1H), 5.03-5.09 (m, 2H), 5.85 (m, 1H), 5.89 (d, 1H, J = 7.9 Hz, NH), 6.96 (m, 3H,
aromatics); 13C NMR (CDCl3, 500 MHz): δ 23.18, 29.71, 34.45, 37.16, 52.38, 53.06,
116.47, 122.47, 128.18, 131.23, 132.03, 133.70, 135.70, 148.01, 169.35, 169.61, 171.94.
Anal. calcd. for C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found: C, 63.90; H, 6.68; N,
4.32.
(S)-Methyl 2-acetamido-3-(4-acetoxy-3-(3-methylbut-2-enyl)phenyl)propanoate (8,
C19H25NO5): To a solution of compound 7 (0.23 g, 0.72 mmol) in anhydrous
dichloromethane (36 ml) was added successively 2-methyl-2-butene (4 ml) and Grubbs’
second generation catalyst (0.018 g, 0.021 mmol) under nitrogen atmosphere. The
solution was stirred for 24 h at room temperature and concentrated under vacuum.
Column chromatography of the dark brown oily material, eluting with ethyl
acetate:hexane (2:3) gave compound 8 as a light yellow solid (0.21 g, 84%). Yield: 0.21
g, 84%; mp 81-82 oC; [α]D25 -59.7 (c. 0.22, CHCl3). IR (neat): 3288, 3061, 2951, 1735,
1649, 1539, 1492, 1370, 1185, 1164 cm-1; 1H NMR (CDCl3, 500 MHz): δ 1.69 (s, 3H),
1.74 (s, 3H), 1.99 (s, 3H, NCOCH3), 2.30 (s, 3H, COCH3), 3.10 (m, 2H), 3.25 (d, 2H, J =
6

7.3 Hz), 3.72 (s, 3H, OCH3), 4.87 (m, 1H), 5.29 (m, 1H), 5.92 (d, 1H, J = 9.7 Hz, NH),
6.93 (m, 3H, aromatics); 13C NMR (CDCl3, 500 MHz): δ 17.82, 23.14, 25.77, 28.59,
29.71, 37.15, 52.31, 53.03, 121.38, 122.31, 127.76, 130.83, 133.41, 133.61, 147.96,
169.41, 169.59, 171.96. Anal. calcd. for C19H25NO5: C, 65.69; H, 7.25; N, 4.03. Found:
C, 65.63; H, 7.30; N, 3.97.
(S)-2-Acetamido-3-(4-hydroxy-3-(3-methylbut-2-enyl)phenyl)propanoic acid (1,
C16H21NO4): To a solution of compound 8 (0.16 g, 0.46 mmol) in a mixture of
tetrahydrofuran, methanol and water (10 ml, in 3:1:1 ratio) was added lithium hydroxide
monohydrate (0.096 g, 2.3 mmol) and the mixture was stirred for 3 h at room
temperature. The solvent was evaporated and residue was diluted with chloroform (20
ml) and washed with 1M hydrochloric acid (3 ml). The organic layer was dried over
anhydrous sodium sulfate, concentrated under vacuum and passed over a plug of silica,
eluting with methanol:dichloromethane (0.5:9.5) to afford compound 1 as a colorless
solid (0.092 g, 69%). The spectral data of 1 coincided with literature values.[12]
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGMENTS
The financial support from KFUPM through grant No: SB131009 and research facilities
provided by KFUPM are gratefully acknowledged.
7

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Scheme 1. Synthesis of tyrosine derivative 1.
10

Figure 1 Chemical structure of tyrosine derivative 1.
11