Two simple and alternative approaches for the synthesis of anticancer active goniothalamin

Article abstract of DOI:10.24820/ark.5550190.p010.461

Two alternative and straightforward routes were developed for the construction of (R)-goniothalamin, a natural anticancer agent. The first method starts with (R)-glycidol involving stereoselective (partial) reduction of alkyne and sulfoxide Julia-Lythgoe

Full text of DOI:10.24820/ark.5550190.p010.461

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Two simple and alternative approaches for the synthesis of anticancer active
goniothalamin
Manchala Narasimhulu,*a S. Siva Prasad,a Rama Moorthy Appa,a Jangam Lakshmidevi,a and Katta
Venkateswarlu*a
aLaboratory for Synthetic & Natural Products Chemistry, Department of Chemistry, Yogi Vemana University,
Kadapa 516003, India
Email: kvenkat@yogivemanauniversity.ac.in
This article is dedicated to the fond memory of Dr. Yenamandra Venkateswarlu for his support,
encouragement and his contribution to synthetic and natural products chemistry
Received 12-30-2017
Accepted 03-28-2018
Published on line 05-27-2018
Abstract
Two alternative and straightforward routes were developed for the construction of (R)-goniothalamin, a
natural anticancer agent. The first method starts with (R)-glycidol involving stereoselective (partial) reduction
of alkyne and sulfoxide Julia-Lythgoe olefination as key steps. Second method deals with the synthesis of (R)-
goniothalamin from 2,3-O-isopropylidene-D-glyceraldehyde with partial reduction of nitrile and Still-Gennari
stereoselective olefination as critical steps. These two methods with simple sequence of standard organic
reactions may be adopted for the sophomore or junior's courses in organic chemistry.
Keywords: (R)-Goniothalamin, anti-cancer active, two strategies, (R)-glycidol, 2,3-O-isopropylidene-D-
glyceraldehyde
DOI: https://doi.org/10.24820/ark.5550190.p010.461
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Introduction
Nature is the source for several bio-potent natural products and are the base for the development of
numerous medicinally or pharmaceutically active compounds.1 Natural products with styryl δ-lactones possess
interesting biological activities such as anticancer, antimicrobial, antimalarial, antilarvicidal and etc.5,6 The
genus Goniothalamus is a rich source of styryl 5- or 6-membered lactones.6,7 Goniothalamin (1) is prototypical
example of styryl δ-lactones, was initially isolated in 1967 from dried bark of Cryptocarya caloneura (Scheff.).8
Later it was found in several plants, for example in Goniothalamus velutinus,9 Cryptocarya moschata,10
Bryonopsis laciniosa,11 and Alyxia schlechteri.12 Goniothalamin was assigned initially (S)-configuration,8 but,
revised as (R)-configuration after the synthesis of both the enantiomers.13 Goniothalamin shows a variety of
biological activities such as anti-cancer,14,15,16 anti-microbial,17,18 anti-inflammatory and antinociceptive,19,20
antiproliferative,20,21 plant growth inhibition activity,22 larvae antifeedant or larvicidal,23 etc. activities. The
activity studies of 1 and its related compounds was revealed by the presence of their side chain.7,21
Since it was reported the synthesis of 1 in 1979 by Meyer13 several reports appeared16,21,24-32 because
of its significant biological properties. Some of the reported syntheses suffers from the requirement of large
quantity of hazardous reagents24,25 or expensive catalysts/auxiliaries26 or with low overall yields31,32 etc.
Although, some efficient protocols were developed, it is still in demand to develop new/improved synthetic
protocols to enhance the scope and possibility of starting materials with simple reactions. In this process we
report here, two alternative routes for the synthesis of 1, involving simple reaction sequences.
Results and Discussion
Most of the literature approaches were appeared by C3-C4 disconnection and/or C7-C8 disconnection24-29 or
some of them by hetero Diels-Alder30 or nucleophilic intramolecular cyclization.31 The synthetic strategy that
we adopted for the synthesis of 1 is represented in the following Scheme (Scheme 1) and is based on the
disconnection of both the C3-C4 and C7-C8 double bonds to simple and commercially available chiral
precursor, (R)-glycidol (4) or 2,3-O-isopropylidene-D-glyceraldehyde (9).
The retrosynthetic approach (Scheme 1) revealed that the target compound 1 may be achieved in two
different ways. In the first route lactone 2 is the key intermediate to furnish goniothalamin (1). The lactone 2
could be obtained from ester 3, and is possible to derive from the commercially available (R)-glycidol, 4. In
another route, 1 may be obtained from the aldehyde 6, which in turn obtained from the 2,3-O-isopropylidine-
D-glyceraldehyde 9.
Scheme 1. Retrosynthetic analysis of (R)-goniothalamin (1).
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At the beginning of the first route (Scheme 2) we have conducted the protection reaction of (R)-
glycidol (4) with p-methoxybenzyl bromide (PMB-Br) in the presence of NaH33 and obtained PMB ether, 10 in
95% yield. Then the compound 10 was subjected for nucleophilic ring opening of epoxide with ethyl propiolate
in the presence of n-BuLi and BF3·Et2O,34 to give homopropargilic alcohol, 3 in an yield of 90%.
Scheme 2. Synthesis of 1 from (R)-glycidol (4).
The alkyne function of 3 was then partially and stereoselectively reduced to (Z)-olefin, 11 in 95% yield
under Lindlar's hydrogenation condition (Pd/CaCO3, H2).35 The (Z)-olefin (11) obtained on treatment with
pyridinium p-toluenesulfonate (PPTS)36 under reflux in CHCl3 was provided cyclized product (lactone), 12 in
92% yield. The PMB ether group of 12 was then uninstalled successfully with DDQ in CHCl3:H2O (8:1) at room
temperature37 and the deprotected alcohol 2 was obtained in 94% yield.
Compound 2 was converted into 1 by Swern oxidation followed by olefin synthesis in one-pot. In this
connection several attempts were made for the preparation of 1. In one attempt, we have oxidized 2 under
Swern oxidation conditions [(COCl)2, CH2Cl2, DMSO, Et3N, −78 °C, 30 min)] into its corresponding aldehyde A
(Figure 1), and added a solution of B (Figure 1) in THF and KHMDS at −78 °C to afford 1 with only 20% yield
(Julia-Kocienski olefination).28,38 In another attempt we have used sulfoxide modified Julia-Lythgoe
procedure39 to react Swern oxidation product (A) with benzyl phenyl sulfone (C) (Figure 1) to give
goniothalamin (1) in 80% yield. This step revealed that the final step of the reported procedure for the
construction of 1, by Pospíšil and Markó.28
Figure 1. Structures of compounds A, B and C.
We have started the second route (Scheme 3) by a Wittig olefination40 reaction of 2,3-O-
isopropylidene-D-glyceraldehyde (9) with benzyltriphenylphosphonium bromide in the presence of n-BuLi to
obtain olefin, 8 in 90% yield as 8:2 ratio of E:Z isomers and the E-isomer has been separated by column
chromatography was used for further step. The acetonide function of E-isomer (8) was uninstalled to 1,2-diol,
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13 (96% yield) with 2M HCl in a mixture of H2O and THF (2:8) was subjected for selective protection
(tosylation) of primary alcoholic function using (n-butyl)2SnO (catalytic amount), tosyl chloride and
triethylamine (TEA)41 to furnish compound 14 in 82% yield. Tosylate, 14 was used for nucleophilic substitution
reaction with KCN in aq. ethanol42 to furnish β-cyanohydrin, 7 (90% yield), was used to react with tert-
butyldimethylsilyl chloride (TBS-Cl) in the presence of imidazole40 to give TBS protected cyanohydrin, 15 in
95% yield.
Scheme 3. Synthesis of 1 from 2,3-O-isopropylidene-D-glyceraldehyde (9).
Compound 15 was partially reduced to aldehyde, 6 (72% yield) by using diisobutylaluminium hydride
(DIBAL-H) in CH2Cl2 at −78 °C.43 Aldehyde, 6 was subjected for stereoselective olefination under Still-Gennari
conditions44,45 to provided cis-olefin 16 in 85% yield. The TBS function of 16 was uninstalled with tetra-n-
butylammonium fluoride (TBAF)46 to give compound 5 (82% yield), which was on reflux in benzene with p-
toluenesulfonic acid (p-TSA)47 yielded the target compound (lactone) goniothalamin (1) in 78% yield.
The first method has been developed with the reaction sequence; etherification (protection), epoxide
ring opening, partial and stereoselective reduction (Lindlar's alkyne hydrogenation), lactonization (ester
formation), deprotection, oxidation and stereoselective (sulfone) olefin synthesis. The second method involves
the Wittig olefination, ketal hydrolysis, tosylation (protection), nucleophilic replacement, silyl ether formation
(protection), nitrile partial reduction, stereoselective (Still-Gennari) olefination and cyclic ester formation
(lactonization). These straightforward sequences may be used as the teaching exercise for sophomore or
junior's courses in organic chemistry to educate on anti-cancer agents.
Conclusions
In summary, we have developed two independent routes for the synthesis of goniothalamin, a significant anti-
cancer agent. Simple reactions with high yields in each step, use of commercially available chiral starting
materials and inexpensive reagents are the notable advantages of the present methods. These methods with
simple sequence of a variety of organic transformations may be adopted for the sophomore or junior's
courses in organic chemistry.
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Experimental Section
General. Solvents were dried over standard drying agents and distilled prior to their use. The reagents and
starting materials were purchased from Aldrich and Acros were used without further purification unless
otherwise stated. All moisture-sensitive reactions were carried out under nitrogen. Organic portion after
workup was dried over anhydrous Na2SO4 and concentrated below 40 °C in vacuo. All column chromatographic
1
separations were performed using silica gel (Acme’s 60-120 mesh). H NMR (200 MHz & 300 MHz) and 13C
NMR (50 MHz and 75 MHz) spectra were measured with a Varian Gemini FT-200 MHz & Bruker Avance 300
MHz with tetramethylsilane (TMS) as an internal standard in CDCl3. Coupling constant (J) values were given in
Hz. IR spectra were recorded on a Perkin-Elmer IR-683 spectrophotometer with NaCl optics. Optical rotations
were measured with Horiba high sensitive polarimeter SEPA-300 at 25o. Mass spectra were recorded on
Agilent Technologies 1100 Series (Agilent Chemistation Software).
(R)-2-[(4-Methoxybenzyloxy)methyl]oxirane (10). To a stirred solution of NaH (1.24 g, 54 mmol) in THF (50
ml) at 0 oC was added (R)-glycidol 4 (2 g, 27 mmol) in dry THF (10 ml). After 20 min, p-methoxybenzyl bromide
(PMB-Br) (5.94 g, 29.7 mmol) was added drop wise and stirred for 3h at room temperature (r.t.). After
completion, the reaction was quenched with water and extracted into AcOEt (3 x 30 ml). The combined
organic layer was dried over anhyd. Na2SO4 and concentrated in vacuo to give crude product, which was
purified over silica gel column chromatography (CC) by using AcOEt:PE (1:9) as eluent to afford the epoxide 10
25
(4.98 g, 95% yield) as a viscous liquid. [α]D = +3.2° (c = 1.5, CHCl3); IR (neat): 3028, 2954, 1597, 1490, 1092,
762; 1H NMR (300 MHz, CDCl3): 7.21 (d, J 8.0 Hz, 2 H), 6.81 (d, J 8.0 Hz, 2 H), 4.51−4.41 (m, 2 H), 3.76 (s, 3 H),
3.64 (dd, J 3.0, 11.3 Hz, 1 H,), 3.35 (dd, J 5.2, 11.3 Hz, 1 H), 3.10−3.05 (m, 1 H), 2.72 (t, J 4.5, 9.0 Hz, 1 H),
2.54−2.51 (m, 1 H); 13C NMR (75 MHz, CDCl3): 159.2, 129.8, 129.3, 113.7, 72.8, 70.4, 55.1, 50.7, 44.1; LC-MS:
217 ([M + Na] +).
Ethyl (R)-6-(4-methoxybenzyloxy)-5-hydroxyhex-2-ynoate (3). To a cooled (-78 °C) solution of ethyl propiolate
(2.02 g, 20.6 mmol) in dry THF (25 ml) was added n-BuLi (1.6M, 12.9 ml, 20.6 mmol) drop wise and stirred for
15 min, then added BF3·Et2O (2.61 ml, 20.6 mmol) and continued stirring for an additional 15 min. Once the
formation of dark brown alkyneborane was observed, a solution of epoxide 10 (2 g, 10.3 mmol) in THF (10 ml)
o
was added and stirred for 30 min at -78 °C. After completion, the reaction was quenched at −78 C by the
addition of saturated Na2SO4 (20 ml) and the reaction mixture was extracted with AcOEt (3 x 30 ml). The
combined organic phase was washed with brine and dried over anhyd. Na2SO4 and concentrated to give crude
mass, which was purified by CC (silica gel) using AcOEt:PE (1:9) as an eluent to give the compound 3 (2.71 g,
25
90% yield) as an oily compound. [α]D = +18.2o (c = 1, CHCl3); IR (neat): 3451, 2912, 2865, 2238, 1709, 1612,
1
1513, 1254, 1076, 823; H NMR (300 MHz, CDCl3): 7.25 (d, J 8.0 Hz, 2 H), 6.85 (d, J 8.0 Hz, 2 H), 4.45 (s, 2 H),
4.15 (q, 2 H), 3.98−3.90 (m, 1 H), 3.82 (s, 3 H), 3.55−3.42 (m, 2 H), 3.10 (brs, 1 H), 2.58 (d, 2 H), 1.28 (t, 3 H); 13C
NMR (75 MHz, CDCl3): 171.2, 159.4, 153.6, 129.8, 129.5, 113.9, 85.4, 74.8, 73.1, 72.4, 68.3, 55.3, 23.8, 14.06;
LC-MS: 315 ([M + Na] +).
Ethyl (R,Z)-6-(4-methoxybenzyloxy)-5-hydroxyhex-2-enoate (11). To a solution of compound 3 (2.6 g, 8.9
mmol) and quinoline (200 µl) in benzene (20 ml) was added Pd/CaCO3 (200 mg) and flushed with hydrogen gas
and stirred for 1h under hydrogen atmosphere and the progress of reaction was ensured by thin layer
chromatography (TLC). After completion of the reaction, catalyst was filtered, concentrated and purified on CC
25
(silica gel) using AcOEt:PE (2:8) as an eluent to afford the (Z)-acrylate 11 (2.49 g, 95% yield) as a liquid. [α]D
=
+5.6o (c = 0.5, CHCl3); IR (neat): 3448, 2958, 1716, 1632, 1512, 1458, 1076, 823; 1H NMR (300 MHz, CDCl3): 7.19
(d, J 7.8 Hz, 2 H), 6.81 (d, J 7.9 Hz, 2 H), 6.42−6.33 (m, 1 H); 5.86 (d, J 11.3, 1 H), 4.43 (s, 2 H), 4.15 (q, 2 H),
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3.89−3.78 (m, 1 H), 3.72 (s, 3 H), 3.58−3.45 (m, 2 H), 2.64−2.38 (m, 2 H), 1.42 (t, J 6.4 Hz, 3 H); 13C NMR (75
MHz, CDCl3): 167.6, 158.4, 146.9, 129.9, 129.6, 122.9, 113.8, 74.3, 73.6, 68.9, 60.1, 54.7, 32.4, 14.0; HRMS:
calcd. for C16H22O5 [M + H] + 295.1523, found 295.1498.
(R)-6-[(Benzyloxy)methyl]-5,6-dihydropyran-2-one (12). Compound 11 (1 g, 3.65 mmol) was dissolved in
CHCl3 (20 ml) and added pyridinium p-toluenesulfonate (PPTS) (0.73 g, 3.65 mmol) and refluxed for 4h. After
completion of the reaction as ensured by TLC, water was added and extracted with CHCl3 (3 x 30 ml). The
combined organic layer was washed with brine, dried over anhyd. Na2SO4 and concentrated. The resulted
crude product was purified over silica gel CC using AcOEt:PE (2:8) as an eluent to afford the α-pyrone, 12 (776
25
1
mg, 92% yield) as a liquid. [α]D = −8.2o (c = 1, CHCl3); IR (neat): 2928, 1716, 1390, 1264, 1083; H NMR (300
MHz, CDCl3): δ = 7.26 (d, J 8.1 Hz, 2 H); 6.93−6.80 (m, 3 H), 5.99 (d, J 11.0 Hz, 1 H), 4.64−4.54 (m, 1 H), 4.52 (s, 2
H), 3.79 (s, 3 H), 3.65 (d, J 5.1 Hz, 2 H), 2.55−2.32 (m, 2 H); 13C NMR (75 MHz, CDCl3): 163.6, 159.3, 144.8,
129.3, 121.1, 113.8, 73.2, 70.4, 55.2, 26.1; HRMS: calcd. for C14H16O4 [M + Na] + 271.2738, found 271.2725.
(R)-5,6-Dihydro-6-(hydroxymethyl)pyran-2-one (2). To a stirred solution of α-pyrone, 12 (720 mg, 2.9 mmol)
in CH2Cl2/H2O (8:2) was added DDQ (1.31 g, 5.8 mmol) and stirred for 1h at r.t. After the completion as
ensured by TLC, the reaction mixture was quenched with saturated aq. NaHCO3, added CH2Cl2 and extracted
into CH2Cl2 (2 x 100 ml). The combined organic layer was dried over anhyd. Na2SO4 and concentrated to give
crude product, was purified over silica gel CC using AcOEt:PE (1:1) to afford pure compound 2 (352 mg, 94%
25
yield) as an oily substance. [α]D = +22.8o (c = 1, CHCl3); IR (neat): 3415, 2927, 1715, 1390, 1262, 1083, 1039;
1H NMR (300 MHz, CDCl3): 6.96−6.88 (m, 1 H), 5.98 (d, J 11.0 Hz, 1 H), 4.56−4.48 (m, 1 H), 3.82−3.68 (m, 2 H),
3.35 (brs, 1 H), 2.68−2.53 (m, 1 H), 1.38−2.24 (m, 1 H); 13C NMR (75 MHz, CDCl3): 164.3, 145.7, 120.5, 78.4,
63.3, 25.1; LC-MS: 129 ([M + H] +).
Goniothalamin [(R)-5,6-dihydro-6-styrylpyran-2-one] (1). Compound 1 was synthesized from 2 by the
reported procedure28 as follows.
To a stirred solution of oxalyl chloride (93 µl, 1.25 mmol) in CH2Cl2 (5 ml) was added a solution of
dimethylsulfoxide (132 µl, 1.87 mmol) in CH2Cl2 (2 ml) at −78 oC under nitrogen atmosphere. After 15 min, (R)-
5,6-dihydro-6-(hydroxymethyl)pyran-2-one (2) (80 mg, 0.63 mmol) was added and the reaction mixture was
stirred for further 30 min at the same temperature.
In another flask a solution of sulfoxide (benzyl phenyl sulfone) (110 mg, 0.62 mmol) in dry THF (6.2 ml, 0.1M
o
solution) was cooled to −78 C and lithium diisopropylamide (LDA) (340 µl, 2M solution in THF, 0.672 mmol)
was added drop wise. The color of the reaction mixture changed from light yellow to orange red. After stirring
o
the mixture at −78 C for 30 min, aldehyde (A) obtained in Swern oxidation in THF was added drop wise and
the mixture was stirred for an additional 2h at −78 oC. Benzoyl chloride (78 µl, 0.672 mmol) in dry THF (0.5 mL)
o
was added. The resultant mixture was stirred for 30 min at −78 C and then allowed to warm to r.t. over 1h
and stirred for additional 30 min at r.t. Me2N(CH2)3NH2 (119 µl, 0.672 mmol) was added to this and the
resultant suspension was stirred for 10 min at r.t. The mixture was diluted with 6 ml of Et2O/H2O (1:1) and the
layers formed were separated. The aqueous layer was extracted with Et2O (3 x 10 ml). The combined organic
layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give the crude
product, which was used without purification for the next step (reductive elimination). To a solution of SmI2
(24.5 ml, 0.1M THF solution, 4 eq.) was added HMPA (425 µl, 2.48 mmol) and the mixture was cooled to −78
oC. The crude product (246 mg, 0.612 mmol) in dry THF (0.5 mL) was added drop wise and the resulting
o
mixture was stirred at −78 C for additional 30 min. Then, saturated aq. NH4Cl (15 ml) was added and the
whole mixture was allowed to warm to r.t. The layers were separated and the aqueous phase was extracted
with Et2O (3 x 20 ml). The combined organic layers were washed with 10% aq. Na2S2O3 (15 ml), water (15 ml)
and brine (15 ml), dried over Na2SO4 and evaporated under reduced pressure. The crude product was then
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purified by silica gel CC using AcOEt:PE (2:8) as eluent to afford compound 1 as white solid with 80% yield in
25
two sequential steps (Swern oxidation followed by sulfoxide Julia-Lythgoe olefination reaction). [α]D
=
+168.2o (c = 1.5, CHCl3) [lit.48 [α]D25 = +170.3o (c = 1.38, CHCl3)]; m.p. 80-83 C [lit.48 m.p. 81-82 C]; IR (neat):
3052, 3027, 2924, 1725, 1242, 814, 693; 1H NMR (300 MHz, CDCl3): 7.36−7.27 (m, 5 H), 6.88 (dt, J 4.3, 9.6 Hz, 1
H), 6.68 (d, J 15.8 Hz, 1 H), 6.23 (dd, J 6.2, 15.8 Hz, 1 H), 6.05 (d, J 9.8 Hz, 1 H), 2.54−2.48 (m, 2 H); 13C NMR (75
MHz, CDCl3): 164.1, 144.9, 135.2, 133.2, 128.6, 128.1, 126.7, 125.4, 121.2, 77.9, 30.07; LC-MS: 223 ([M + Na] +).
(S)-2,2-Dimethyl-4-styryl-1,3-dioxolane (8). To a suspension of [PPh3CH2Ph]Br (6.64 g, 15.4 mmol) in dry THF
(50 ml) was added n-BuLi (1.6M in hexane, 9.6 ml, 15.4 mmol) at 0 oC and stirred for 15 min. Then a solution of
ketal, 9 (2 g, 15.4 mmol) in THF (10 ml) was added drop wise and the mixture was allowed to stir for an
o
o
o
additional 0.5 h at 0 C. The reaction was quenched with saturated NH4Cl (40 ml) and extracted with diethyl
ether (3 x 50 ml). The ether solution was washed with brine and dried over anhyd. Na2SO4. After removal of
solvent, the crude product obtained was purified on a silica gel CC with AcOEt:PE (2:98) (eluent) to afford pure
compound 8 (2.82 g, 90% yield) as a liquid as 8:2 mixture of geometric isomers (both are separated and 2.25 g,
25
of E-isomer obtained in 72% yield). [α]D = +30.2o (c = 1.5, CHCl3); IR (neat): 3062, 3024, 2986, 2929, 2860,
1610, 1498, 1296, 1060; 1H NMR (300 MHz, CDCl3): 7.35−7.17 (m, 5 H), 6.61 (d, J 15.8 Hz, 1 H), 6.10 (dd, J 7.5,
15.8 Hz, 1 H), 4.65−4.57 (m, 1 H), 4.12−4.08 (m, 1 H), 3.63 (t, J 7.5 Hz, 1 H), 1.44 (s, 3 H), 1.39 (s, 3 H); 13C NMR
(75 MHz, CDCl3): 136.1, 133.2, 128.4, 127.8, 126.5, 126.4, 109.3, 77.0, 69.3, 26.6, 25.7; LC-MS: 205 ([M + H] +).
(2S,E)-4-Phenylbut-3-ene-1,2-diol (13). To a stirred solution of compound 8 (2.1 g, 10.3 mmol) in 15 mL of
THF/H2O (8:2), was added 2N HCl (4 mL) drop wise and stirred the solution at r.t. for 2h. After completion, the
reaction was quenched with saturated NaHCO3 and extracted with AcOEt (3 x 25 mL). The combined organic
layer was dried over anhyd. Na2SO4 and concentrated to a give a crude mass, which was purified over silica gel
o
CC eluting with AcOEt:PE (1:1) to afford the pure diol 13 as a white solid (1.62 g, 96% yield); m.p. 62-64 C;
25
1
[α]D = +6.2o (c = 1.5, CHCl3); IR (neat): 3469, 3260, 3080, 2936, 1639, 1598, 1490, 1079, 776; H NMR (300
MHz, CDCl3): 7.26−7.15 (m, 5 H), 6.55 (d, J 15.8 Hz, 1 H), 6.09 (dd, J 6.0, 15.8 Hz, 1 H), 4.38−4.32 (m, 1 H), 4.14
(brs, 2 H), 3.66 (dd, J 3.0, 11.3 Hz, 1 H), 3.51 (dd, J 8.3, 11.3 Hz, 1 H); 13C NMR (75 MHz, CDCl3): 136.2, 133.2,
129.6, 128.6, 128.3, 127.5, 68.6, 66.1; LC-MS: 187 ([M + Na] +).
(S,E)-2-Hydroxy-4-phenylbut-3-enyl 4-methylbenzenesulfonate (14). To a stirred solution of diol 13 (1.5 g,
9.14 mmol), catalytic amount of dibutyltin oxide (15 mg) and triethylamine (2.88 ml, 22.8 mmol) in
o
dichloromethane (30 ml) was added at 0 C. After 15 min tosyl chloride (1.74 g, 9.14 mmol) in CH2Cl2 (10 ml)
was added drop wise and stirred the reaction mixture for 4h at r.t. After completion, the reaction mixture was
diluted with water (50 ml) and extracted into CH2Cl2 (3 x 50 ml). The combined organic portion was washed
with brine solution and dried over anhyd. Na2SO4. After the evaporation of solvent under reduced pressure
the crude residue was purified on a silica gel CC by eluting with AcOEt:PE (3:7) to afford the compound 14 as a
white solid (2.38 g, 82% yield); m.p. 138-141 oC; [α]D25 = +1.6o (c = 1, CHCl3). IR (neat): 3449, 2924, 1640, 1494,
1359, 1176, 1096; 1H NMR (300 MHz, CDCl3): 7.77 (d, J 7.5 Hz, 2 H), 7.28−7.18 (m, 7 H); 6.62 (d, J 15.8 Hz, 1 H),
6.00 (dd, J 6.0, 15.8 Hz, 1 H), 4.54−4.49 (m, 1 H), 4.10−4.05 (m, 1 H), 3.96−3.90 (m, 1 H), 2.95 (brs, 1 H), 2.41 (s,
3 H); 13C NMR (75 MHz, CDCl3): 144.8, 135.6, 135.3, 132.9, 129.7, 128.6, 128.3, 127.9, 126.7, 123.5, 75.3, 71.4,
21.6; LC-MS: 319.2 ([M + H] +); elemental anal calcd. for C17H18O4S (218.23) C 64.13, H 5.71, S 10.07; found C
64.38, H 5.64, S 10.18.
(R,E)-3-Hydroxy-5-phenylpent-4-enenitrile (7). To a cooled (0 oC) solution of tosylate, 14 (2.3 g, 7.23 mmol) in
60% aqueous ethanol (30 ml) was added KCN (0.71 g, 10.84 mmol) and was stirred at r.t. for 10h. After
completion of the reaction, ethanol was evaporated under vacuum and diluted with water (20 ml), extracted
with AcOEt (3 x 30 ml) and the combined organic phase was washed with brine and dried over anhyd. Na2SO4
and the solvent was removed under reduced pressure to get crude residue. The crude product was subjected
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silica gel CC using AcOEt:PE (3:7) as an eluent to afford the compound 7 (1.12 g, 90% yield) as colorless oil.
25
1
[α]D = −8.25o (c = 1, CHCl3); IR (neat): 3447, 3028, 2252, 1653, 1494, 752; H NMR (300 MHz, CDCl3):
7.32−7.20 (m, 5 H), 6.61 (d, J 15.8 Hz, 1 H), 5.68 (dd, J 6.0, 15.8 Hz, 1 H), 4.82−4.68 (m, 1 H), 3.39 (brs, 1 H),
2.54−2.51 (m, 2 H); 13C NMR (75 MHz, CDCl3): 135.5, 132.4, 128.5, 128.2, 128.1, 126.6, 117.3, 68.3, 26.1; LC-
MS: 174.18 ([M + H] +); elemental anal calcd. for C11H11NO (173.28) C 76.28, H 6.40, N 8.09; found C 76.14, H
6.47, N 8.19.
o
(3R,4E)-3-(tert-Butyldimethylsilanyloxy)-5-phenylpent-4-enenitrile (15). To a cooled solution (0 C) of cyano
compound 7 (1.1 g, 6.35 mmol) and imidazole (1.08 g, 15.89 mmol) in CH2Cl2 (20 ml) was added drop wise,
tert-butyldimethylsilyl chloride (TBS-Cl) (0.96 g, 6.35 mmol). After completion, the reaction mixture was
diluted with water (15 ml) and extracted with CH2Cl2 (3 x 25 ml). The combined organic layer was washed with
brine (10 ml), dried over anhyd. Na2SO4 and concentrated under vacuum to furnish the crude residue. The
obtained crude residue was purified by flash CC on silica using AcOEt:PE (1:9) as an eluent to afford pure
compound 15 (1.73 g, 95% yield) as a colourless oil. [α]D25 = +5.6o (c = 1.5, CHCl3); IR (neat): 3068, 3027, 2932,
2856, 2254, 1632, 1470, 1172; 1H NMR (300 MHz, CDCl3): 7.39−7.25 (m, 5 H), 6.63 (d, J 15.6 Hz, 1 H), 6.17 (dd, J
6.6, 15.8 Hz, 1 H), 4.61−4.54 (m, 1 H), 2.57 (d, J 6.4 Hz, 2 H), 0.93 (s, 9 H), 0.15 (s, 3 H), 0.09 (s, 3 H); 13C NMR
(75 MHz, CDCl3): 135.8, 131.6, 129.2, 128.5, 128.06, 126.5, 117.2, 69.5, 27.5, 25.6, 18.0, −4.4, −5.0; LC-MS:
326.2 ([M + K] +), elemental anal calcd. for C17H25NOSi (287.17) C 71.03, H 8.77, N 4.87; found C 71.16, H 8.68,
N 4.89.
(3R,4E)-3-(tert-Butyldimethylsilanyloxy)-5-phenylpent-4-enal (6). To a stirred solution of compound 15 (1.7 g,
o
5.92 mmol) in CH2Cl2 (20 ml) was added DIBAL-H (4.21 ml, 20 wt.% in sol.) slowly for 15 min at −78 C and the
o
reaction mixture was stirred for 30 min at −78 C. After completion, the reaction mixture was quenched with
saturated sodium potassium tartrate solution (15 ml). The reaction mixture was stirred vigorously at r.t. for
additional 1h and extracted with CH2Cl2 (3 x 25 ml). The combined organic layer was washed with brine, dried
over anhyd. Na2SO4 and solvent was removed under vacuum to give a crude product, which was purified by
silica gel CC using AcOEt:PE (2:50) as eluent to afford pure aldehyde, 6 (1.24 g, 72% yield) as a colorless oil.
25
1
[α]D = +5.3o (c = 0.5, CHCl3); IR (neat): 3047, 2928, 2842, 1733, 1590, 1476, 1370, 1188, 1043, 823; H NMR
(300 MHz, CDCl3): 9.83 (s, 1 H), 7.38−7.16 (m, 5 H), 6.49 (d, J 15.8 Hz, 1 H), 5.70 (dd, J =6.2, 15.8 Hz, 1 H),
5.22−5.12 (m, 1 H), 2.80−2.54 (m, 2 H), 0.81 (s, 9 H), −0.06 (s, 3 H), −0.13 (s, 3 H); 13C NMR (75 MHz, CDCl3):
201.5, 136.6, 134.5, 129.5, 128.7, 128.6, 127.5, 65.1, 51.4, 25.8, 18.1; LC-MS: 291 ([M + H] +).
(5R,2Z,6E)-5-(tert-Butyldimethylsilanyloxy)-7-phenylhepta-2,6-dienoate (16). To a cooled (0 oC) suspension of
NaH (0.19 g, 8.27 mmol) in dry THF (5 ml) under N2 atmosphere was added bis(2,2,2-trifluoromethyl)
(methoxy carbonylmethyl)phosphonate (0.87 ml, 4.13 mmol) in dry THF (3 ml) and was allowed to stirring for
30 min. Reaction temperature was adjusted to −78 C, then the aldehyde, 6 (1.2 g, 4.13 mmol) was added in
dry THF (5 ml) drop wise over a period of 10 min. The resulting mixture was stirred for 2h at −78 C. After
o
o
completion of the reaction, the reaction mixture was quenched with saturated NH4Cl and extracted into Et2O
(3 x 15 ml). The combined organic phase was dried over anhyd. Na2SO4 and solvent was evaporated under
vacuum to obtain crude product, which was purified by flash CC (silica gel) by eluting with AcOEt:PE (1:9) to
afford the (Z)-acrylate 16 (1.21 g, 85% yield) as light yellow oil. [α]D25 = +16.2o (c = 0.5, CHCl3); IR (neat): 3047,
2928, 2842, 1733, 1590, 1476, 1370, 1188, 1043, 823; 1H NMR (300 MHz, CDCl3): 7.34−7.16 (m, 5 H), 6.46−6.31
(m, 2 H), 5.85 (d, J 11.7 Hz, 1 H), 5.65 (dd, J 6.0, 15.8 Hz, 1 H), 4.76−4.64 (m, 1 H), 3.70 (s, 3 H), 3.14−2.84 (m, 2
H), 0.81 (s, 9 H), −0.11 (s, 3 H), −0.17 (s, 3 H); 13C NMR (75 MHz, CDCl3): 166.7, 146.3, 136.7, 135.3, 128.8,
128.1, 127.0, 120.5, 68.0, 51.0, 37.3, 25.7, 18.0, −4.3, −5.01; HRMS: calcd for C20H30O3Si [M + Na] + 369.2728,
found 369.3167.
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(R,2Z,6E)-5-Hydroxy-7-phenylhepta-2,6-dienoate (5). To a cooled (0 °C) solution of compound 16 (1 g, 2.89
mmol) in dry THF (10 ml) was added drop wise, TBAF (2.89 ml, 2.89 mmol, 1M solution in THF) and the mixture
was stirred for 30 min at r.t.. After completion of the reaction, water (5 ml) was added to the reaction mixture
and extracted with AcOEt (3 x 15 ml). The combined organic phase was washed with brine, dried over anhyd.
Na2SO4 and concentrated to give the crude mass, which was purified by silica gel CC eluting with AcOEt:PE
(2:8) to afford the pure compound 5 (0.551 g, 82% yield) as a liquid. [α]D25 = +11.50o (c = 1, CHCl3); IR (neat):
1
3445, 2928, 1715, 1636, 1452, 1014, 756; H NMR (300 MHz, CDCl3): 7.37−7.26 (m, 5 H), 6.57 (d, J 15.8 Hz, 1
H), 6.41−6.32 (m, 1 H), 5.95 (d, J 11.5 Hz, 1 H), 5.74 (dd, J 6.0, 15.8 Hz, 1 H), 4.75−4.67 (m, 1 H), 3.72 (s, 3 H),
3.10−2.87 (m, 2 H); LC-MS: 233 ([M + H] +).
Goniothalamin [(R)-5,6-dihydro-6-styrylpyran-2-one] (1). To a stirred solution of compound 5 (0.2 g, 0.86
mmol) in benzene (15 ml) was added a catalytic amount of p-toluenesulfonic acid (0.014 mg, 0.08 mmol)
o
under nitrogen atmosphere and reaction mixture was refluxed at 90 C for 1h. Then the reaction mixture was
cooled to r.t., quenched by an addition of solid NaHCO3, the mixture was filtered and the solvent was
evaporated under vacuum to obtain the crude residue, which was purified by flash CC on silica gel by eluting
with AcOEt:PE (4:6) to afford goniothalamin (1) (0.134g, 78% yield) as a white solid. The spectroscopic data
were identical with the data given at Section 2.6.
Acknowledgements
Authors are highly thankful to CSIR, New Delhi for financial support through grant no. 02(0196)/14/EMR-II and
Senior Research Fellowship.
Supplementary Material
Copies of 1H and 13C NMR spectra were given at Supplementary Material.
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