Total Synthesis of 5-Hydroxygoniothalamin

Article abstract of DOI:10.1055/s-0037-1610997

The total synthesis of 5-hydroxygoniothalamin is achieved from commercially available l -xylose. The α,β-unsaturated-δ-lactone core is constructed in very good yield by utilizing one-carbon and two-carbon cis -Wittig olefinations and δ-lactonization using Yamaguchi conditions. Subsequent Grubbs cross-metathesis followed by desilylation results in 5-hydroxygoniothalamin.

Full text of DOI:10.1055/s-0037-1610997

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
A
en
S. R. Patpi et al.
Paper
Synthesis
Total Synthesis of 5-Hydroxygoniothalamin
Santhosh Reddy Patpia,b
Guangyi Jinb,c
Srinivas Kantevari*a,d
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9-
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6
5-
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5
OH
OH
O
O
steps
HO
steps
O
OH
O
O
BnO
BnO
HO
O
O
a Department of Crop Protection Chemicals, CSIR-Indian
Institute of Chemical Technology, Hyderabad 500 007,
Telangana, India
OH
L-xylose
O
b School of Pharmaceutical Sciences, Shenzhen University
Health Science Center, Shenzhen 518 060, Guangdong,
P. R. of China
c Cancer Research Center, Shenzhen University Health
Science Center, Shenzhen 518 060, Guangdong, P. R. of
China
d Academy of Scientific and Innovative Research, CSIR-In-
dian Institute of Chemical Technology, Hyderabad 500
007, Telangana, India
kantevari@yahoo.com
ksriniva@iict.res.in
Received: 13.07.2018
Accepted after revision: 05.09.2018
Published online: 01.10.2018
world. 5-Hydroxygoniothalamin is a synthetic derivative of
the styryl-lactone natural product goniothalamin, a sec-
ondary metabolite isolated from the root and stem of Goni-
othalamus macrophyllus.8 Harris et al.9 have described the
only synthesis of 5-hydroxygonoithalamin from furfural.
We are interested in synthesizing natural products con-
taining the 5,6-dihydro-2H-pyran-2-one template. Herein,
we describe an efficient synthesis of 5-hydroxygoniothala-
min through a cross-metathesis strategy10 as the key reac-
tion.
DOI: 10.1055/s-0037-1610997; Art ID: ss-2018-z0469-op
Abstract The total synthesis of 5-hydroxygoniothalamin is achieved
from commercially available L-xylose. The α,β-unsaturated-δ-lactone
core is constructed in very good yield by utilizing one-carbon and two-
carbon cis-Wittig olefinations and δ-lactonization using Yamaguchi
conditions. Subsequent Grubbs cross-metathesis followed by desilyla-
tion results in 5-hydroxygoniothalamin.
Key words C1 Wittig reaction, C2 Wittig reaction, Yamaguchi reac-
tion, cross-metathesis, 5-hydroxygoniothalamin
Ph
O
Natural products are a rich source of potential drugs
and drug leads, and they have played a vital role in drug
discovery over the past few decades. The majority of new
drugs have been discovered from naturally occurring sub-
stances and their derivatives.1 Therefore, natural products
and their molecular architectures have a long tradition as
valuable templates for the study of chemical biology and
drug discovery.2 Among them, α,β-unsaturated-δ-lactones
are found as structural subunits in a wide variety of natural
products possessing diverse biological activities.3 Many
natural products from various plants and fungi share a 5-
oxygenated-5,6-dihydro-2H-pyran-2-one moiety as a com-
mon structural motif.4 Structure–activity relationship stud-
ies suggested that the α,β-unsaturated-δ-lactone moiety is
essential for displaying biological activity and probably acts
as a Michael acceptor in the presence of protein functional
groups.5,6 Such lactones also often serve as intermediates
for the synthesis of natural products, for example, 5-
hydroxygoniothalamin (1), crassalactone A (2), phomopsol-
ide B (3) and phomalactone (4) (Figure 1).7 Because of their
structural complexities and biological activities, the syn-
thesis of these types of molecules in optically pure form has
attracted the attention of several groups from across the
OH
O
OH
O
O
O
O
OH
1 5-hydroxygoniothalamin
2 (+)-crassalactone A
O
O
OH
OH
O
O
O
O
OH
3 (+)-phomopsolide B
4 (+)-phomalactone
Figure 1 Examples of natural products containing an α,β-unsaturated-
δ-lactone moiety
Our retrosynthetic analysis for 5-hydroxygoniothalamin
is depicted in Scheme 1. The key intermediate, lactone 5,
was visualized as the final precursor of the target molecule,
and could be obtained from the ester 6 using Yamaguchi
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
S. R. Patpi et al.
Paper
Synthesis
OH
OBn
OH
O
O
HO
OH
OH
L-xylose
O
BnO
HO
BnO
O
O
O
O
O
O
O
1
5
6
7
Scheme 1 Retrosynthetic analysis for the synthesis of 5-hydroxygoniothalamin
reaction conditions. The ester 6 could be derived from the
carbohydrate precursor L-xylose through reactions involv-
ing one-carbon and two-carbon Wittig olefinations.
The synthesis of the target molecule 1 was initiated
with acetonide protection of commercially available L-xy-
diastereomeric ratio (Z/E). After separation of the diastereo-
mers, the ester (Z)-6a was treated with LiOH·H2O to gave
acid 13, which was subjected to δ-lactonization using
Yamaguchi reaction conditions, i.e., 2,4,6-trichlorobenzoyl
chloride and pyridine, to give α,β-unsaturated-δ-lactone 5
in excellent yield (86%). Debenzylation of 5 with AlCl3 led to
free hydroxy olefinic product 14 in 84% yield.
The cross-metathesis of olefin 5 with styrene using
Grubbs second-generation catalyst in dichloromethane un-
der reflux conditions for 24 hours afforded 15 in 90% yield
(Scheme 3). Unfortunately, deprotection of 15 with various
debenzylating agents such as DDQ, Pd(OH)2, lithium/naph-
thalene, AlCl3, TiCl4, FeCl3 and TMSI did not result in the tar-
get compound, but instead decomposed the starting mate-
rial. Even the cross-metathesis of the free hydroxy olefinic
compound 14 with styrene using Grubbs first- or second-
generation catalyst did not provide the desired target com-
pound. The olefinic compound 14 did not react with sty-
rene even when the reaction was run for more than 48
hours or with increasing the temperature using different
solvents. Although the complete mechanism is not under-
lose to afford 1,2-O-isopropylidene-α-L-xylofuranose
8
(Scheme 2) via a literature protocol.11 The primary alcohol
8 was selectively protected with TBSCl in CH2Cl2 using im-
idazole as the base to give 9 in 94% yield. The secondary al-
cohol group in 9 was protected with benzyl bromide using
NaH in THF to give compound 10 in 58% yield. Deprotection
of 10 with TBAF in THF gave the primary alcohol 11 in 97%
yield. Alcohol 11 was efficiently oxidized with oxalyl chlo-
ride, DMSO and triethylamine to provide the corresponding
aldehyde, which was immediately reacted with PPh3CH3Br,
a one-carbon Wittig salt, to give alkene 7 in 85% yield. Hy-
drolysis of 7 with 4% H2SO4 yielded secondary diol 12. Oxi-
dative cleavage of 12 with NaIO4 in MeOH/H2O (9:1) gave an
aldehyde, which was immediately treated with PPh3=CHCOOEt,
a two-carbon Wittig ylide, in MeOH at –10 °C to furnish a
mixture of 6a and 6b in excellent yield (79%) and an 80:20
O
O
HO
TBSO
BnO
O
TBSO
O
HO
OH
OH
L-xylose
d
c
O
a
b
O
HO
O
HO
HO
O
O
O
10
9
8
OH
OH
O
O
O
HO
BnO
e
f
g
+
O
O
O
OH
BnO
BnO
BnO
BnO
O
O
O
OH
O
11
7
O
12
6b
6a
Z/E = 80:20
OH
OBn
OH
j
i
h
BnO
HO
O
O
O
O
O
14
5
13
Scheme 2 Reagents and conditions: (a) (i) acetone, CuSO4, cat. H2SO4, 24 h, 86%; (ii) MeOH, 3 M H2SO4, 6 h, 94%; (b) TBSCl, imidazole, CH2Cl2, 6 h, 94%;
(c) NaH, THF, 0 °C to r.t., then BnBr, 16 h, 58%; (d) TBAF, THF, 0 °C to r.t., 1 h, 97%; (e) (COCl)2, DMSO, Et3N, –78 °C, 2 h, then PPh3CH3Br, t-BuOK, THF,
0 °C to r.t., 1 h, 85%; (f) 4% H2SO4, THF, reflux, 10 h, 71%; (g) NaIO4, MeOH/H2O (9:1), 0 °C to r.t., then PPh3=CHCOOEt, MeOH, –10 °C, 1 h, 79%
(Z/E = 80:20) (over two steps); (h) LiOH·H2O, THF/H2O (1:1), 1 h, 82%; (i) 2,4,6-trichlorobenzoyl chloride, pyridine, 2 h, 86%; (j) AlCl3, m-xylene, CH2Cl2,
0 °C, 1 h, 84%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
S. R. Patpi et al.
Paper
Synthesis
In conclusion, we have developed an efficient synthesis
of 5-hydroxygoniothalamin (1) in 4.8%, 14 steps from the
readily available starting material, L-xylose. The key reac-
tions involved in the described synthesis of 5-hydroxygoni-
othalamin are a one-carbon Wittig olefination, a two-car-
bon Wittig olefination with a simple C-2 Wittig ylide, δ-lac-
tone formation using Yamaguchi conditions and a cross-
metathesis. The total synthesis of similar molecules using
this strategy is currently being explored in our laboratory.
OH
OH
Grubbs II
Ph
+
O
O
CH2Cl2, reflux
O
O
14
48 h
1
OBn
OBn
Grubbs II
CH2Cl2, reflux
O
O
Ph
+
24 h
O
O
5
15
All solvents and reagents were purified by standard techniques. Reac-
tions were performed in oven-dried round-bottomed flasks. Crude
products were purified by column chromatography on Merck silica
gel (60–120 mesh) and flash chromatographic separation was carried
out using Merck silica gel (230–400 mesh). Thin-layer chromatogra-
phy was performed using Merck 60 F-254 plates; the samples were
made visual by exposure to UV light and/or by exposure to a methan-
olic acidic solution of p-anisaldehyde (developed on a hot-plate). Or-
ganic solutions were concentrated on a rotary evaporator at 40–45 °C.
Melting points were obtained using a Fischer–Johns melting point ap-
paratus and are uncorrected. Optical rotations were obtained on a Di-
gipol 760 polarimeter. Infrared (IR) spectra were recorded on a Per-
kin–Elmer 683 spectrophotometer. NMR spectra were recorded in
CDCl3 on a Bruker 300 or Varian Unity 400 NMR spectrometer. Chem-
ical shifts (δ) are quoted in ppm and are referenced to tetramethylsi-
lane (TMS) as the internal standard. Coupling constants (J) are quoted
in hertz (Hz). The multiplicities: s, d, dd, ddd, dt, t, q, and m refer to
singlet, doublet, doublet of doublets, doublet of doublet of doublets,
doublet of triplets, triplet, quartet, and multiplet, respectively. Mass
spectra (ESI) were recorded on a Micromass VG-7070H mass spec-
trometer. High-resolution mass spectra (ESI) were obtained using ei-
ther a Finnegan MAT1020B TOF or a VG-Auto Speck-M double focus-
ing spectrometer.
Scheme 3 Synthetic analysis of 5-hydroxygoniothalamin
stood,12 a plausible explanation for the failure could be that
in substrate 14, the Ru metal of the Grubbs catalyst might
be interacting parallelly with the olefin as well as with the
proximal OH group, making the metal complex more stable.
Hence it may be preventing the olefin undergoing metathe-
sis with the styrene unit. In compound 5, such an interac-
tion with the OH is prevented and is probably electronically
favored to proceed via Grubbs-catalyzed olefin metathesis.
However, deprotection of benzyl group is cumbersome in
the presence of a double bond and resulted in decomposi-
tion or multiple products. A further literature search12 sug-
gested that TBS might be an efficient protecting group and
several natural products were synthesized successfully us-
ing the Grubbs catalyst in the presence of this silyl group.
To complete the synthesis of 5-hydroxygoniothalamin,
compound 14 was converted into silyl ether 16 by protec-
tion of the alcohol with TBSCl/imidazole in dichlorometh-
ane. Silylated 16 was further transformed into alkene 17 in
89% yield using styrene and the Grubbs second-generation
catalyst in dichloromethane under reflux conditions for 24
hours. Deprotection of the TBS group with TBAF afforded
the target compound 5-hydroxygoniothalamin (1) in 62%
yield (Scheme 4). The spectral and physical data of 5-hy-
droxygoniothalamin were in agreement with the reported
data.9
(3aS,5S,6R,6aS)-5-(Hydroxymethyl)-2,2-dimethyltetrahydrofu-
ro[2,3-d][1,3]dioxol-6-ol (8)
A mixture of L-xylose (8 g, 53.3 mmol), anhydrous CuSO4 (21.2 g,
133.3 mmol), and concentrated H2SO4 (0.6 mL) in acetone (150 mL)
was stirred at 25 °C for 24 h. The mixture was filtered and the solid
washed with acetone. The filtrate was neutralized with K2CO3 and the
resulting white solid was removed by filtration. The acetone was then
removed in vacuo to give a yellow syrup, which was dissolved in H2O
and extracted with CHCl3 (2 × 150 mL). The combined organic layers
were washed with brine (2 × 60 mL), dried over anhydrous Na2SO4,
filtered and concentrated under reduced pressure. The residue was
purified by trituration with hexane to afford 10.5 g (86%) of the pure
intermediate diacetonide as a colorless viscous liquid.
OTBS
OH
a
b
O
O
O
O
16
14
[α]D29 +2.8 (c 0.4, CHCl3).
IR (neat): 2989, 2935, 1378, 1201, 1082, 1015 cm–1
.
OTBS
OH
1H NMR (300 MHz, CDCl3): δ = 6.01 (d, J = 3.5 Hz, 1 H, H-1), 4.53 (d,
J = 3.5 Hz, 1 H, H-2), 4.30 (d, J = 1.8 Hz, 1 H, H-3), 4.13–4.06 (m, 2 H,
H-5, H-5′), 4.06–3.99 (m, 1 H, H-4), 1.50 (s, 3 H, CH3), 1.45 (s, 3 H,
CH3), 1.39 (s, 3 H, CH3), 1.33 (s, 3 H, CH3).
c
O
O
O
O
1
17
13C NMR (75 MHz, CDCl3): δ = 111.5, 105.1, 97.4, 84.6, 73.1, 71.5, 60.1,
28.8, 26.6, 26.1, 18.6.
MS (ESI): m/z = 253 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C11H18O5Na: 253.10464; found:
Scheme 4 Reagents and conditions: (a) TBSCl, imidazole, CH2Cl2, 12 h,
72%; (b) styrene, Grubbs II catalyst, CH2Cl2, reflux, 24 h, 89%; (c) TBAF,
THF, 0 °C to r.t., 0.5 h, 62%.
253.10413.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
S. R. Patpi et al.
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Synthesis
To a stirred solution of the diacetonide (10.3 g, 44.7 mmol) in MeOH
(120 mL) was added 3 M H2SO4 (120 mL) and the mixture was stirred
for 6 h at r.t. (TLC monitoring). MeOH was removed in vacuo and the
aqueous fraction was extracted with CHCl3 (3 × 100 mL). The com-
bined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure to give 8.0 g (94%)
of pure compound 8 as a colorless liquid.
1H NMR (500 MHz, CDCl3): δ = 7.39–7.26 (m, 5 H, Ar-H), 5.90 (d,
J = 3.7 Hz, 1 H, H-1), 4.66 (d, J = 11.9 Hz, 1 H, ArCH), 4.62–4.56 (m, 2 H,
ArCH, H-2), 4.28–4.22 (m, 1 H, H-4), 3.99 (d, J = 2.9 Hz, 1 H, H-3),
3.94–3.82 (m, 2 H, H-5, H-5′), 1.50 (s, 3 H, CH3), 1.31 (s, 3 H, CH3), 0.89
(s, 9 H, 3 × CH3), 0.06 (s, 6 H, 2 × CH3).
13C NMR (75 MHz, CDCl3): δ = 137.7, 128.4, 127.7, 127.5, 111.6, 105.0,
82.5, 81.3, 80.8, 72.2, 60.0, 26.8, 26.2, 18.2, –5.3, –5.4.
[α]D29 –20.7 (c 0.3, CHCl3).
MS (ESI): m/z = 395 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H35O5Si: 395.22483; found:
IR (neat): 3423, 2986, 2937, 1380, 1216, 1073, 1014 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.00 (d, J = 3.5 Hz, 1 H, H-1), 4.54 (d,
J = 3.5 Hz, 1 H, H-2), 4.34 (s, 1 H, OH), 4.23–4.01 (m, 3 H, H-3, H-4, H-
5), 3.95 (d, J = 2.6 Hz, 1 H, H-5′), 2.59–2.42 (m, 1 H, OH), 1.49 (s, 3 H,
CH3), 1.33 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 111.7, 104.7, 85.5, 78.7, 76.7, 61.0, 26.7,
26.1.
395.22479.
[(3aS,5S,6R,6aS)-6-(Benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl]methanol (11)
To a stirred solution of compound 10 (5.5 g, 13.9 mmol) in THF (30
mL) was added TBAF (4 mL, 1 M in THF) at 0 °C and the reaction was
allowed to stir at r.t. for 1 h. A saturated solution of NH4Cl was added
to the reaction mixture and the resulting solution was extracted with
EtOAc (3 × 40 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was passed through a silica gel column (20%
EtOAc in hexane) to afford 3.8 g (97%) of pure compound 11 as a col-
orless liquid.
MS (ESI): m/z = 213 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C8H14O5Na: 213.07334; found:
213.07282.
(3aS,5S,6R,6aS)-5-[(tert-Butyldimethylsilyloxy)methyl]-2,2-di-
methyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (9)
To a stirred solution of 1,2-O-isopropylidene-L-xylo-furanose 8 (7.5 g,
39.4 mmol) in anhydrous CH2Cl2 (75 mL) was added imidazole (6.7 g,
98.6 mmol) and tert-butyldimethylsilyl chloride (6.5 g, 43.4 mmol) at
0 °C under a nitrogen atmosphere. After an overnight reaction at r.t.,
the mixture was quenched with ice-cold H2O (40 mL) and extracted
with EtOAc (3 × 80 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated under re-
duced pressure. The crude residue was passed through a silica gel col-
umn (10% EtOAc in hexane) to afford 10.5 g (94%) of pure compound 9
as a colorless liquid.
[α]D29 +20.7 (c 0.2, CHCl3).
IR (neat): 3454, 2985, 2934, 1377, 1215, 1076, 1016 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.41–7.28 (m, 5 H, Ar-H), 6.00 (d,
J = 3.8 Hz, 1 H, H-1), 4.72 (d, J = 12.0 Hz, 1 H, PhCH), 4.65 (d, J = 3.8 Hz,
1 H, H-2), 4.50 (d, J = 12.0 Hz, 1 H, PhCH), 4.28 (q, J = 4.5 Hz, 1 H, H-4),
4.02 (d, J = 3.5 Hz, 1 H, H-3), 3.99–3.92 (m, 1 H, H-5), 3.91–3.82 (m, 1
H, H-5′), 2.14 (dd, J = 8.6, 3.5 Hz, 1 H, OH), 1.49 (s, 3 H, CH3), 1.34 (s, 3
H, CH3).
.
13C NMR (75 MHz, CDCl3): δ = 137.0, 128.6, 128.1, 127.6, 111.7, 105.0,
82.7, 82.4, 80.0, 71.8, 60.9, 26.7, 26.2.
[α]D29 +25.0 (c 0.2, CHCl3).
IR (neat): 3446, 2933, 2858, 1378, 1254, 1216, 1075, 1013 cm–1
.
MS (ESI): m/z = 303 [M + Na]+.
1H NMR (300 MHz, CDCl3): δ = 5.96 (d, J = 3.7 Hz, 1 H, H-1), 4.51 (d,
J = 3.7 Hz, 1 H, H-2), 4.40 (d, J = 2.6 Hz, 1 H, OH), 4.37–4.29 (m, 1 H, H-
4), 4.18–4.07 (m, 3 H, H-3, H-5 and H-5′), 1.49 (s, 3 H, CH3), 1.33 (s, 3
H, CH3), 0.90 (s, 9 H, 3 × CH3), 0.11 (s, 6 H, 2 × CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C15H20O5Na: 303.12029; found:
303.11984.
(3aS,5S,6R,6aS)-6-(Benzyloxy)-2,2-dimethyl-5-vinyltetrahydrofu-
ro[2,3-d][1,3]dioxole (7)
13C NMR (75 MHz, CDCl3): δ = 111.4, 104.9, 85.5, 78.0, 77.0, 62.3, 26.7,
26.1, 25.6, 18.0, –5.5, –5.6.
To a solution of oxalyl chloride (3.17 g, 2.11 mL, 25 mmol) in anhyd
CH2Cl2 (10 mL) at –78 °C was added dropwise anhyd DMSO (2.9 g,
2.65 mL, 37.5 mmol) in CH2Cl2 (10 mL). After 30 min, alcohol 11 (3.5
g, 12.5 mmol) in CH2Cl2 (20 mL) was added over 10 min giving a copi-
ous white precipitate. After stirring for 1 h at –78 °C, Et3N (6.3 g, 8.68
mL, 62.5 mmol) was added at the same temperature and the mixture
was allowed to warm to r.t. Finally, the mixture was quenched with
H2O (30 mL). The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (3 × 30 mL). The combined organic layer
was washed with brine (40 mL), dried over Na2SO4, and the solvent
was removed under reduced pressure to give the corresponding alde-
hyde as a pale yellow oil which was used in the next step without pu-
rification.
{[(3aS,5S,6R,6aS)-6-(Benzyloxy)-2,2-dimethyltetrahydrofuro[2,3-
d][1,3]dioxol-5-yl]methoxy}(tert-butyl)dimethylsilane (10)
To a stirred suspension of freshly activated NaH (1.77 g, 74 mmol)
(60% w/v dispersion in mineral oil) in anhydrous THF (25 mL) was
added alcohol 9 (7.5 g, 24.6 mmol) in anhydrous THF (50 mL) at 0 °C.
After 30 min, benzyl bromide (4.18 g, 24.6 mmol) was added and the
reaction mixture brought to r.t. and stirred for 16 h. Ice pieces were
added to quench the reaction. The THF layer was separated and the
aqueous layer extracted with Et2O (3 × 60 mL). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude residue was passed
through a silica gel column (6% EtOAc in hexane) to afford 5.6 g (58%)
of pure compound 10 as a colorless liquid.
The aldehyde in anhyd THF (20 mL) was added to a mixture of meth-
yltriphenylphosphonium iodide (11.0 g, 31 mmol, 2.5 equiv) and po-
tassium tert-butoxide (2.81 g, 24.8 mmol, 2.0 equiv) in anhyd THF (50
mL) at 0 °C. The reaction mixture was allowed to warm to r.t., stirred
for 1 h, then quenched with H2O (10 mL) and extracted with Et2O
(2 × 25 mL). The combined organic layers were washed with brine,
[α]D29 +77.5 (c 0.1, CHCl3).
IR (neat): 2929, 2856, 1461, 1378, 1252, 1216, 1078, 839 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

E
S. R. Patpi et al.
Paper
Synthesis
dried over anhydrous Na2SO4, and concentrated under reduced pres-
sure. The residue was passed through a silica gel column (7% EtOAc in
hexane) to afford 3.0 g (85%) of pure compound 7 as a colorless liquid.
gel column chromatography (10% EtOAc in hexane) to afford 1.33 g
(79%) of the cis/trans products (Z/E = 80:20) as colorless liquids. Z =
1.1 g (63%) and E = 270 mg (16%).
[α]D29 +46.4 (c 0.25, CHCl3).
IR (neat): 2987, 2934, 1612, 1513, 1248, 1076, 1031 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.41–7.25 (m, 5 H, Ar-H), 6.12–5.93
[m, 2 H, H-1, H-5 (olefinic)], 5.50–5.38 (m, 1 H, H-6), 5.37–5.28 (m, 1
H, H-6′), 4.73–4.59 (m, 3 H, ArCH, H-4), 4.55 (d, J = 12.0 Hz, 1 H,
ArCH), 3.88 (d, J = 3.2 Hz, 1 H, H-3), 1.51 (s, 3 H, CH3), 1.33 (s, 3 H,
CH3).
13C NMR (75 MHz, CDCl3): δ = 137.4, 132.2, 128.3, 127.7, 127.5, 119.0,
111.4, 104.7, 83.3, 82.8, 81.5, 72.0, 26.7, 26.1.
MS (ESI): m/z = 299 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C16H20O4Na: 299.12472; found:
Ethyl (4S,5S,Z)-4-(Benzyloxy)-5-hydroxyhepta-2,6-dienoate (6a)
[α]D29 –32.8 (c 0.2, CHCl3).
.
IR (neat): 3439, 3065, 2930, 1725, 1379, 1254, 1097, 1052 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.41–7.27 (m, 5 H, Ar-H), 6.18 (dd,
J = 11.7, 8.8 Hz, 1 H, H-3), 6.02 (dd, J = 11.7, 0.9 Hz, 1 H, H-2), 5.98–
5.81 (m, 1 H, H-6), 5.34 (dt, J = 3.0, 1.3 Hz, 1 H, H-7), 5.20 (dt, J = 2.8,
1.3 Hz, 1 H, H-7′), 5.13–5.01 (m, 1 H, H-5), 4.60 (d, J = 11.5 Hz, 1 H,
ArCH), 4.48 (d, J = 11.5 Hz, 1 H, ArCH), 4.17 (q, J = 7.1 Hz, 3 H, H-4,
OCH2), 2.84 (d, J = 4.5 Hz, 1 H, OH), 1.28 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 165.9, 146.3, 137.7, 136.2, 128.3, 127.9,
123.7, 116.8, 77.4, 75.0, 71.7, 60.5, 14.1.
MS (ESI): m/z = 299 [M + Na]+.
299.12538.
HRMS (ESI): m/z [M + Na]+ calcd for C16H20O4Na: 299.12538; found:
(2R,3S,4S,5S)-4-(Benzyloxy)-5-vinyltetrahydrofuran-2,3-diol (12)
299.12495.
To a stirred solution of compound 7 (2.85 g, 10.3 mmol) in THF (30
mL) was added 4% H2SO4 (30 mL) and the mixture was refluxed over-
night. After completion of the reaction, the THF was evaporated and
the acid neutralized with K2CO3. The aqueous layer was extracted
with EtOAc (3 × 50 mL). The combined organic layers were washed
with brine, dried over anhydrous Na2SO4, and concentrated under re-
duced pressure. The residue was passed through a silica gel column
(30% EtOAc in hexane) to afford 1.72 g (71%) of pure compound 12 as
a colorless liquid, which solidified upon storage in a refrigerator.
Ethyl (4S,5S,E)-4-(Benzyloxy)-5-hydroxyhepta-2,6-dienoate (6b)
[α]D29 +111.8 (c 0.2, CHCl3).
IR (neat): 3455, 2983, 2930, 1719, 1370, 1274, 1177, 1031 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.42–7.28 (m, 5 H, Ar-H), 6.84 (dd,
J = 15.8, 6.8 Hz, 1 H, H-3), 6.09 (dd, J = 15.8, 1.0 Hz, 1 H, H-2), 5.86–
5.75 (m, 1 H, H-6), 5.37 (dt, J = 2.8, 1.5 Hz, 1 H, H-7), 5.25 (dt, J = 2.7,
1.3 Hz, 1 H, H-7′), 4.67 (d, J = 11.4 Hz, 1 H, ArCH), 4.41 (d, J = 11.5 Hz, 1
H, ArCH), 4.23 (q, J = 7.0 Hz, 2 H, OCH2), 4.15–4.05 (m, 1 H, H-5), 3.88
(dt, J = 6.8, 1.2 Hz, 1 H, H-4), 2.68 (d, J = 3.5 Hz, 1 H, OH), 1.32 (t, J = 7.0
Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 165.7, 143.8, 137.2, 135.3, 128.5, 128.0,
127.9, 124.6, 117.9, 81.6, 74.5, 71.6, 60.6, 14.1.
MS (ESI): m/z = 299 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C16H20O4Na: 299.12538; found:
.
Mp 53–55 °C; [α]D29 –3.1 (c 0.3, CHCl3).
IR (KBr): 3272, 2926, 2880, 1355, 1130, 1046, 930 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H, Ar-H), 6.15–5.90
(m, 1 H, H-5), 5.52 (d, J = 4.2 Hz, 1 H, H-1), 5.48–5.25 (m, 1 H, H-6),
4.77–4.68 (m, 1 H, H-6′), 4.67–4.55 (m, 3 H, H-4, ArCH2), 4.23 (dd,
J = 3.8, 3.3 Hz, 1 H, H-2), 3.98 (dd, J = 4.8, 3.2 Hz, 1 H, H-3).
13C NMR (75 MHz, CDCl3): δ = 137.6, 133.4, 128.3, 127.6, 127.5, 118.6,
95.7, 84.4, 79.9, 75.3, 72.0.
299.12496.
MS (ESI): m/z = 259 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C13H16O4Na: 259.09408; found:
(4S,5S,Z)-4-(Benzyloxy)-5-hydroxyhepta-2,6-dienoic Acid (13)
259.09367.
To a stirred solution of ester compound 6a (950 mg, 3.4 mmol) in a
1:1 mixture of THF and H2O (10 mL) was added LiOH·H2O at r.t. and
the resulting mixture was stirred for 1 h. After evaporation of the THF,
the aqueous layer was acidified with 1 M HCl and extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed with
brine, dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The residue was passed through a short silica gel column
(50% EtOAc in hexane) to afford 700 mg (82%) of pure compound 13
as a colorless liquid.
Ethyl (4S,5S,Z)-4-(Benzyloxy)-5-hydroxyhepta-2,6-dienoate (6a)
and Ethyl (4S,5S,E)-4-(Benzyloxy)-5-hydroxyhepta-2,6-dienoate
(6b)
To a stirred solution of diol 12 (1.5 g, 6.3 mmol) in MeOH/H2O (36 mL,
9:1) was added sodium periodate (2.7 g, 12.7 mmol) at 0 °C. Next, the
reaction mixture was brought to r.t. and stirred for 1 h. The reaction
mixture was filtered through a Celite bed, the solid washed with
MeOH and the filtrate concentrated under reduced pressure. The
crude residue was diluted with H2O, neutralized with K2CO3 and ex-
tracted with EtOAc (3 × 40 mL). The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and concentrated
under reduced pressure to afford the corresponding aldehyde as a
thick syrup which was immediately used in the next step without fur-
ther purification.
[α]D29 –30.0 (c 0.1, CHCl3).
IR (neat): 3447, 2925, 2855, 1728, 1459, 1069 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H, Ar-H), 6.30 (dd,
J = 11.7, 9.0 Hz, 1 H, H-3), 6.06 (dd, J = 11.7, 1.0 Hz, 1 H, H-2), 5.94–
5.84 (m, 1 H, H-6), 5.34 (dt, J = 17.2, 1.3 Hz, 1 H, H-7), 5.22 (dt, J = 10.5,
1.3 Hz, 1 H, H-7′), 5.06 (ddd, J = 17.2, 5.7, 1.0 Hz, 1 H, H-5), 4.61 (d,
J = 11.4 Hz, 1 H, ArCH), 4.50 (d, J = 11.5 Hz, 1 H, ArCH), 4.12 (t, J = 7.1
Hz, 1 H, H-4).
13C NMR (75 MHz, CDCl3): δ = 170.3, 148.7, 137.5, 135.9, 128.4, 127.9,
122.8, 117.3, 75.0, 71.9.
MS (ESI): m/z = 271 [M + Na]+.
To a stirred solution of the aldehyde in MeOH (25 mL) at –10 °C was
added (ethoxycarbonylmethylene)triphenylphosphorane (3.2 g, 9.3
mmol) and the resulting mixture was stirred for 1 h at the same tem-
perature. After consumption of aldehyde, the solvent was evaporated
under reduced pressure and the crude residue was purified by silica
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
S. R. Patpi et al.
Paper
Synthesis
(5S,6S)-5-(Benzyloxy)-6-vinyl-5,6-dihydro-2H-pyran-2-one (5)
13C NMR (75 MHz, CDCl3): δ = 162.7, 143.4, 137.0, 135.8, 134.5, 128.6,
128.5, 128.3, 128.1, 127.8, 126.7, 123.0, 122.3, 80.2, 71.8, 69.2.
MS (ESI): m/z = 329 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C20H18O3Na: 329.11482; found:
329.11361.
To a stirred solution of acid 13 (680 mg, 2.74 mmol) in pyridine (4
mL) was added 2,4,6-trichlorobenzoyl chloride (0.73 g, 3 mmol) at
0 °C and the reaction mixture was stirred for 2 h at r.t. The reaction
mixture was diluted with Et2O. The organic layer was washed with 7%
aqueous NaHCO3 solution, dried over Na2SO4 and concentrated under
reduced pressure. The residue purified by silica gel column chroma-
tography (10% EtOAc in hexane) to afford 540 mg (86%) of pure com-
pound 5 as a yellowish oil.
(5S,6S)-5-(tert-Butyldimethylsilyloxy)-6-vinyl-5,6-dihydro-2H-
pyran-2-one (16)
To a stirred solution of 14 (200 mg, 1.4 mmol) in anhyd CH2Cl2 (8 mL)
was added imidazole (240 mg, 3.5 mmol) and tert-butyldimethylsilyl
chloride (230 mg, 1.5 mmol) at 0 °C under a nitrogen atmosphere. Af-
ter an overnight reaction at r.t., the mixture was quenched with ice-
cold H2O (10 mL) and extracted with EtOAc (2 × 12 mL). The com-
bined organic layers were washed with brine, dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The crude residue
was passed through a silica gel column (10% EtOAc in hexane) to af-
ford 260 mg (72%) of pure compound 16 as a colorless liquid.
[α]D29 +110.4 (c 0.2, CHCl3)
IR (neat): 2923, 2853, 1718, 1246, 1048 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.43–7.28 (m, 5 H, Ar-H), 6.84 (dd,
J = 9.8, 4.5 Hz, 1 H, H-4), 6.12 (m, 2 H, H-3, H-7), 5.51 (dt, J = 17.1, 1.3
Hz, 1 H, H-8), 5.43 (dt, J = 10.7, 1.3 Hz, 1 H, H-8′), 4.98–4.88 (m, 1 H,
H-6), 4.62 (s, 2 H, ArCH2), 4.17 (dt, J = 4.5, 0.5 Hz, 1 H, H-5).
13C NMR (75 MHz, CDCl3): δ = 162.6, 143.2, 137.0, 131.4, 128.5, 128.2,
127.7, 123.0, 119.5, 80.1, 71.6, 69.0.
MS (ESI): m/z = 253 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C14H14O3Na: 253.08352; found:
.
[α]D29 +99.2 (c 0.5, CHCl3).
IR (neat): 2930, 2857, 1735, 1251, 1107 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.78 (dd, J = 9.8, 4.5 Hz, 1 H, H-4),
6.12–5.95 (m, 2 H, H-3, H-7), 5.51–5.34 (m, 2 H, H-8, H-8′), 4.87–4.74
(m, 1 H, H-6), 4.35 (t, J = 4.5 Hz, 1 H, H-5), 0.88 (s, 9 H, 3 × CH3), 0.09
(s, 6 H, 2 × CH3).
13C NMR (75 MHz, CDCl3): δ = 162.9, 145.3, 132.0, 121.7, 119.4, 81.3,
64.1, 25.5, 18.0, –4.4, –4.8.
253.08310.
(5S,6S)-5-Hydroxy-6-vinyl-5,6-dihydro-2H-pyran-2-one (14)
To a suspension of AlCl3 (0.58 g, 4.3 mmol) in CH2Cl2 (10 mL) was add-
ed a solution of compound 5 (420 mg, 1.8 mmol) in m-xylene (1 mL)
at 0 °C and the reaction mixture was stirred for 1 h at 0 °C. The mix-
ture was poured into ice-water and extracted with Et2O (3 × 15 mL).
The combined organic layers were washed with brine, dried over an-
hydrous Na2SO4, and concentrated under reduced pressure. The resi-
due was purified through a short silica gel column (22% EtOAc in hex-
ane) to afford 210 mg (84%) of pure compound 14 as a colorless liquid.
[α]D29 +33.6 (c 0.1, CHCl3).
IR (neat): 3402, 2923, 2853, 1721, 1378, 1259, 1091, 1041 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.01 (dd, J = 9.7, 5.4 Hz, 1 H, H-4), 6.12
(d, J = 9.7 Hz, 1 H, H-3), 6.10–6.00 (m, 1 H, H-7), 5.57 (dt, J = 2.4, 1.2
Hz, 1 H, H-8), 5.48 (dt, J = 2.4, 1.2 Hz, 1 H, H-8′), 4.93–4.86 (m, 1 H, H-
6), 4.24 (dd, J = 5.3, 3.0 Hz, 1 H, H-5), 2.75 (br s, 1 H, OH).
MS (ESI): m/z = 255 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H23O3Si: 255.14110; found:
255.14084.
(5S,6S)-5-(tert-Butyldimethylsilyloxy)-6-styryl-5,6-dihydro-2H-
pyran-2-one (17)
.
To a stirred solution of 16 (220 mg, 0.86 mmol) in anhyd CH2Cl2 (6
mL) was added styrene (450 mg, 4.33 mmol). Grubbs II catalyst (73
mg, 0.08 mmol, 10 mol%) was subsequently added in one portion and
the resulting mixture was heated under nitrogen at reflux for 24 h.
The solvent was concentrated under reduced pressure and the residue
purified by silica gel column chromatography (12% EtOAc in hexane)
to afford 250 mg (89%) of pure compound 17 as a colorless solid.
13C NMR (75 MHz, CDCl3): δ = 163.1, 144.4, 131.0, 122.7, 120.1, 80.8,
62.6.
MS (ESI): m/z = 163 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C7H8O3Na: 163.03657; found:
Mp 68–70 °C; [α]D29 +93.7 (c 0.5, CH2Cl2).
IR (KBr): 2928, 2856, 1715, 1383, 1254, 1091, 1050 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.45–7.22 (m, 5 H, Ar-H), 6.83 (dd,
J = 9.8, 4.7 Hz, 1 H, H-4), 6.73 (d, J = 16.2 Hz, 1 H, H-8), 6.37 (dd,
J = 16.2, 6.9 Hz, 1 H, H-7), 6.09 (d, J = 9.8 Hz, 1 H, H-3), 4.98 (ddd,
J = 6.7, 3.5, 1.1 Hz, 1 H, H-6), 4.37 (dd, J = 4.3, 3.96 Hz, 1 H, H-5), 0.88
(s, 9 H, 3 × CH3), 0.09 (s, 3 H, CH3), 0.07 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 163.0, 145.2, 135.8, 134.3, 128.6, 128.2,
126.6, 122.8, 121.8, 81.4, 64.1, 25.5, 17.9, –4.4, –4.8.
163.03662.
(5S,6S)-5-(Benzyloxy)-6-styryl-5,6-dihydro-2H-pyran-2-one (15)
To a stirred solution of 5 (100 mg, 0.4 mmol) in anhyd CH2Cl2 (4 mL)
was added styrene (220 mg, 2.17 mmol). Grubbs II catalyst (36 mg,
0.04 mmol, 10 mol%) was subsequently added in one portion and the
resulting mixture was heated under nitrogen at reflux for 12 h. The
solvent was concentrated under reduced pressure and the residue pu-
rified by silica gel column chromatography (12% EtOAc in hexane) to
afford 120 mg (90%) of pure compound 15 as a colorless solid.
MS (ESI): m/z = 331 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H27O3Si: 331.17240; found:
331.17188.
Mp 58–60 °C; [α]D29 +60.7 (c 0.2, CHCl3).
IR (KBr): 3029, 2924, 2856, 1725, 1581, 1452, 1250, 1092, 1050 cm–1
.
(5S,6S)-5-Hydroxy-6-styryl-5,6-dihydro-2H-pyran-2-one (5-Hy-
droxygoniothalamin) (1)
1H NMR (300 MHz, CDCl3): δ = 7.48–7.27 (m, 10 H, Ar-H), 6.89 (dd,
J = 9.9, 4.5 Hz, 1 H, H-4), 6.79 (d, J = 16.0 Hz, 1 H, H-8), 6.45 (dd,
J = 16.0, 6.7 Hz, 1 H, H-7), 6.16 (d, J = 9.9 Hz, 1 H, H-3), 5.11–5.06 (m, 1
H, H-6), 4.69–4.59 (m, 2 H, ArCH2), 4.19 (t, J = 4.2 Hz, 1 H, H-5).
To a stirred solution of 17 (100 mg, 0.3 mmol) in anhyd THF (2 mL)
was added TBAF (0.36 mmol, 1 M solution in THF) at 0 °C to r.t. The
mixture was stirred for 0.5 h, quenched with Et2O and saturated
aqueous NaHCO3 (15 mL). The phases were separated and the aque-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
S. R. Patpi et al.
Paper
Synthesis
ous layer was extracted with Et2O (3 × 15 mL). The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure. The crude residue was passed
through a silica gel column (30% EtOAc in hexane) to afford 40 mg
(62%) of pure compound 1 as a colorless liquid.
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[α]D29 +60.0 (c 0.1, CH2Cl2).
IR (KBr): 3408, 2923, 2852, 1772, 1454, 767, 699 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.47–7.32 (m, 5 H, Ar-H), 7.04 (dd,
J = 9.7, 5.3 Hz, 1 H, H-4), 6.88 (dd, J = 16.2, 1.0 Hz, 1 H, H-8), 6.39 (dd,
J = 16.0, 6.5 Hz, 1 H, H-7), 6.19 (d, J = 9.7 Hz, 1 H, H-3), 5.08 (ddd,
J = 4.2, 3.0, 1.3 Hz, 1 H, H-6), 4.32 (dd, J = 5.3, 3.0 Hz, 1 H, H-5).
13C NMR (75 MHz, CDCl3): δ = 162.9, 144.4, 135.1, 128.6, 128.5, 126.8,
(6) Rungeler, P.; Castro, V.; Mora, G.; Goren, N.; Vichnewski, W.;
Pahl, H. L.; Merfort, I.; Schmidt, T. J. Bioorg. Med. Chem. 1999, 7,
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125.4, 122.9, 121.5, 80.9, 63.0.
MS (ESI): m/z = 217 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C13H13O3: 217.0859; found:
217.0853.
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Acknowledgment
The authors are grateful to the Director, CSIR-IICT for continuous sup-
port and encouragement. S.R.P. is thankful to CSIR, New Delhi for the
award of a fellowship. This article is also a CSIR-IICT Communication:
IICT/Pubs./2018/258.
Supporting Information
(8) Sam, T. W.; Sew-Yeu, C.; Matsjeh, S.; Gan, E. K.; Razak, D.;
Mohamed, A. L. Tetrahedron Lett. 1987, 28, 2541.
Supporting information for this article is available online at
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(b) Harris, J. M.; O’Doherty, G. A. Tetrahedron 2001, 57, 5161.
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(b) Gupta, P.; Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2004, 45,
849. (c) Yadav, J. S.; Kumar, N. N.; Reddy, M. S.; Prasad, A. R. Tet-
rahedron 2007, 63, 2689. (d) de Fatima, A.; Kohn, L. K.; Antonio,
M. A.; de Carvalho, J. E.; Pilli, R. A. Bioorg. Med. Chem. 2004, 12,
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(g) Wach, J. Y.; Stephan, G.; Kutay, U.; Gademann, K. Bioorg. Med.
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(12) (a) Ogba, O. M.; Warner, N. C.; O’Leary, D. J.; Grubbs, R. H. Chem.
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https://doi.org/10.1055/s-0037-1610997.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G