Chemoenzymatic Access to (+)-Artabotriol and its Application in Collective Synthesis of (+)-Grandiamide D, (-)-Tulipalin B, (+)-Spirathundiol, and (+)-Artabotriolcaffeate

Article abstract of DOI:10.1055/s-0035-1561588

Starting from dimethyl (±)-2-hydroxy-3-methylenesuccinnate chemoenzymatic collective formal/total synthesis of enantiomerically pure bioactive natural products has been described via the advanced level common precursor (+)-artabotriol. An efficient enzymatic resolution with high enantiomeric purity, selective diester to diol reduction, and requisite dehydrative coupling reactions without any racemization are the significant topographies.

Full text of DOI:10.1055/s-0035-1561588

SYNTHESIS
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1
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7
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1
0
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
R. U. Batwal, N. P. Argade
Paper
Synthesis
Chemoenzymatic Access to (+)-Artabotriol and its Application
in Collective Synthesis of (+)-Grandiamide D, (–)-Tulipalin B,
(+)-Spirathundiol, and (+)-Artabotriolcaffeate
O
Ramesh U. Batwal
O
OH
Narshinha P. Argade*
Amano PS, VA
MeO
MeO
4 steps
(57%)
MeO
MeO
HO
acetone, 25 o
72 h
C
OH
OH
OAc
Division of Organic Chemistry, National Chemical Laboratory
(CSIR), Pune 411 008, India
np.argade@ncl.res.in
O
O
(+)-Artabotriol
Dimethyl ( )-2-hydroxy-3-
(+)-2 (54%, 94% ee)
methylenesuccinate (1)
4 steps (12%)
3 steps (23%)
4 steps (13%)
3 steps (14%)
(+)-Grandiamide D
(–)-Tulipalin B
(+)-Artabotriol
(+)-Spirathundiol
(+)-Artabotriolcaffeate
Received: 22.01.2016
Accepted after revision: 24.02.2016
Published online: 12.04.2016
view.6 In continuation of our studies on both cyclic anhy-
drides and derivatives to bioactive natural products7 and ef-
ficient enzymatic resolutions,6a,8 we herein report a facile
chemoenzymatic synthesis of the (+)-artabotriol and its ap-
plication as a fundamental building block in collective for-
mal/total synthesis of four other enantiomerically pure nat-
ural products (Schemes 1–3).
DOI: 10.1055/s-0035-1561588; Art ID: ss-2016-z0053-op
Abstract Starting from dimethyl (±)-2-hydroxy-3-methylenesuccin-
nate chemoenzymatic collective formal/total synthesis of enantiomeri-
cally pure bioactive natural products has been described via the ad-
vanced level common precursor (+)-artabotriol. An efficient enzymatic
resolution with high enantiomeric purity, selective diester to diol reduc-
tion, and requisite dehydrative coupling reactions without any racem-
ization are the significant topographies.
O
OH
OH
O
NH
N
HO
Key words dimethyl (±)-2-hydroxy-3-methylenesuccinate, enzymatic
resolution, reduction, (+)-artabotriol, coupling reactions, collective
synthesis, natural products
H
OH
OH
O
(+)-Grandiamide D (activity unknown)3
O
OH
HO
HO
Nature derives large number of sugar monomers, which
rejoin with other natural products to form broad range of
structurally interesting and biologically important second-
ary metabolites; in addition to the formation of prime es-
sential complex carbohydrates.1 More specifically, the five
carbon bearing sugar (–)-artabotriol has been isolated from
Artabostrys hexapetalus.2 Recently, the (+)-artabotriol de-
rived natural product (+)-grandiamide D has been isolated
from Aglaia gigantean;3 whereas the (+)-artabotriolcaffeate
has been isolated from Ilex pubescens (Figure 1).4 The abso-
lute configuration of (+)-artabotriolcaffeate has been estab-
lished by using modified Mosher’s method. The first total
synthesis of (+)-grandiamide D has been recently reported
in the literature;5 although the synthesis of artabotriol is
still awaited. Simple retrosynthetic analysis revealed that
nature constructs them starting from enantiomerically
pure artabotriol in a stepwise fashion via an appropriate se-
quence of coupling reactions utilizing the naturally occur-
ring putrescine, cinnamic acid, and caffeaic acid. The sci-
ence of collective total synthesis of bioactive natural prod-
ucts is very important for structure activity relationship
studies from lead optimization and drug discovery point of
(+)-Artabotriolcaffeate
(activity unknown)4a
O
OH
O
HO
OH
O
O
OH
HO
HO
O
OH
HO
O
O
OH
O
(–)-Pubescenosides A
(antiplatelet aggregator)4b
OH
HO
OH
(–)-Pubescenosides B
(antiplatelet aggregator)4b
Figure 1 Artabotriol derived natural products
A careful analysis of (+)/(–)-artabotriol structure speci-
fied that the dimethyl (±)-2-hydroxy-3-methylenesuccinate
(1)8a would be a potential precursor for their synthesis via
enzymatic resolution followed by the reduction route
(Scheme 1). The racemic dimethyl 2-hydroxy-3-methylene-
succinate (1) was prepared from dimethyl itaconate via al-
lylic oxidation in two steps by using the known procedure.8a
Accordingly, we systematically studied the Amano PS-cata-
lyzed stereoselective acylation of (±)-alcohol 1 using vinyl
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
R. U. Batwal, N. P. Argade
Paper
Synthesis
O
O
O
O
O
O
O
TBDMSCl
imidazole
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
Amano PS, VA
HCl (2 N), MeOH
0 °C, 2 h (90%)
MeO
MeO
+
CH2Cl2, 25 °C
6 h (94%)
acetone, 25 °C
72 h
OH
OAc
OH
OH
OTBDMS
O
O
O
(−)-3
(
)-1
(−)-1 (46%, 98% ee)
(+)-1
(+)-2 (54%, 94% ee)
OH
HO
OTBDMS
O
dimethoxypropane
TBAF, THF
DIBAL, THF
HO
O
OH
_78 °C, 2 h (72%)
25 °C, 10 h
(93%)
OH
OH
p-TSA, THF
4 h (85%)
(+)-6
(+)-4
(+)-Artabotriol (5)
O
NH2
N
(i) MnO2, CH2Cl2
25 oC, 36 h
H
O
O
O
O
H
N
O
O
N
H
(ii) Ag2O, H2O
25 °C, 1 h (68%)
OH
EDCI, Et3N, CH2Cl2, 25 °C, 4 h (87%)
O
(+)-8
(+)-7
OH
O
p-TSA, MeOH, 0 °C, 2 h
H
HO
N
(77%)
N
H
O
(+)-Grandiamide D (9)
Scheme 1 Chemoenzymatic total synthesis of putrescine bisamide (+)-grandiamide D
acetate (VA) as an acyl donor and obtained the enantiomer-
ically pure (–)-alcohol 1 in 46% yield (98% ee, by HPLC) and
the corresponding (+)-acetate 2 in 54% yield (94% ee, by
HPLC) (Table 1). The obtained stereochemical outcome was
further confirmed by comparison with the reported analyt-
ical and spectral data for both the compounds (–)-1 and (+)-
2.8a Acid-catalyzed hydrolysis of (+)-acetate 2 to the corre-
sponding (+)-alcohol 1 followed by TBDMS-protection pro-
vided (–)-silyl ether 3 in 85% yield over two steps. The
DIBAL reduction of (–)-diester 3 to the corresponding (+)-
diol 4 followed by TBAF induced desilylation supplied the
desired enantiomerically pure (+)-artabotriol (5) in 67%
yield over two steps. The analytical and spectral data ob-
tained for synthetic (+)-artabotriol (5) was in complete
agreement with the reported data for natural product (–)-
artabotriol (5)2 and the chemoenzymatic first synthesis of
(+)-artabotriol (5) was accomplished in five steps in 31%
overall yield. The selective protection of vicinal diol moiety
in compound (+)-5 resulted in (+)-ketal 6 in 85% yield. The
MnO2 oxidation of (+)-allylic alcohol 6 to the corresponding
α,β-unsaturated aldehyde followed by its an immediate sil-
ver oxide-induced oxidation delivered the known α,β-un-
saturated (+)-carboxylic acid 7 in 68% yield. In the above
mentioned reaction, the formed intermediate α,β-unsatu-
rated aldehyde was unstable and hence it was directly sub-
jected to the next oxidation without any purification and
characterization to obtain the corresponding known (+)-
carboxylic acid 7.9 The (+)-acid 7 on EDCI-induced dehydra-
tive coupling reaction with the known requisite putrescine
amide10 formed the corresponding (+)-putrescine diamide
8 in 87% yield. Finally, acid-catalyzed deprotection of a ketal
moiety in (+)-diamide 8 furnished the desired natural prod-
uct (+)-grandiamide D (9) in 77% yield (98% ee by HPLC).
The analytical and spectral data obtained for synthetic
product was in complete agreement with the reported data
for natural product3,5 and the chemoenzymatic synthesis of
(+)-grandiamide D (9) was accomplished in nine steps in
12% overall yield. The natural products (–)-tulipalin B (10)
and (+)-spirathundiol (11) have been isolated from Tulipa
gesneriana and Spiraea thunbergii Sieb. respectively.9,11 As
depicted in Scheme 2, the acid-catalyzed ketal deprotection
in (+)-acid 7 followed by in situ regioselective dehydrative
γ-lactonization to form the (–)-tulipalin B (10) in one step
in 76% yield and the esterification of (+)-acid 7 followed by
O
OH
HCl (1 N ), reflux, 1 h
(76%) (known)9
O
O
O
O
HO
(+)-7
(−)-Tulipalin B (10)
(i) NaH, MeI, HMPA
25 °C, 45 min (64%)
(known)9
OMe
HO
(ii) aq AcOH
85 °C, 90 min (66%)
OH
O
(+)-Spirathundiol (11)
Scheme 2 Formal synthesis of (–)-tulipalin B and (+)-spirathundiol
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
R. U. Batwal, N. P. Argade
Paper
Synthesis
the controlled ketal deprotection to form the (+)-spirathun-
diol (11) in two steps in 42% overall yield are known in the
literature.9
the corresponding (+)-ester 14 in 82% yield. The (+)-ester 14
on treatment with p-TSA in methanol directly furnished the
desired natural product (+)-artabotriolcaffeate (15) in 67%
yield. In the above specified reaction, fortunately both the
deprotection of ketal moiety and the two OMOM groups
took place in one pot and the formed product with four free
hydroxyl groups was quite stable under the set of our reac-
tion conditions. The analytical and spectral data obtained
for synthetic product was in complete agreement with the
reported data for natural product4a and the chemoenzymat-
ic synthesis of (+)-artabotriolcaffeate (15) was accom-
plished in eight steps in 14% overall yield (Scheme 3).
In summary, we have completed the chemoenzymatic
first synthesis of (+)-artabotriol sugar and used it as a po-
tential starting material to accomplish the collective syn-
thesis of enantiomerically pure bioactive natural products
employing a chiral pool strategy. Synthesis of those multi-
functional natural products is noteworthy from their stabil-
ity point of view. Application of enzymatic resolution path-
way also provides an access to antipodes of all the synthe-
sized natural products. The present approach on collective
total synthesis of enantiomerically pure natural and unnat-
ural products will be highly useful for the rational design of
focused mini-libraries of their analogues and congeners for
SAR-studies.
Table 1 Lipase-Catalyzed Resolution of Dimethyl (±)-2-Hydroxy-3-
methylenesuccinate
Entry Solvent
Temp (Time)a
(–)-1: Yield (%) (+)-2: Yield (%)
(ee)b (ee)b
1
2
3
4
5
Benzene–PE
25 °C (24 h)
25 °C (48 h)
25 °C (48 h)
25 °C (72 h)
25 °C (80 h)
74 (ND)c 24 (ND)c
Benzene–PE
Acetone
40 (72)
72 (ND)c
46 (98)
44 (100)
60 (51)
28 (ND)c
54 (94)
56 (92)
Acetone
Acetone
a Reactions were monitored by HPLC.
b Chiral HPLC.
c ND: Not determined.
In the next part of studies, it was envisioned to synthe-
size natural product (+)-artabotriolcaffeate starting from
(+)-artabotriol (5) (Scheme 3). Accordingly, the EDCI-per-
suaded dehydrative coupling of (+)-allylic alcohol 6 with
the methylenedioxy-protected caffeaic acid provided the
corresponding (+)-ester 12 in 84% yield. Acid-catalyzed
deprotection of ketal moiety in compound (+)-12 resulted
into the essential product (+)-13 in 81% yield. Though the
final step of BBr3-promoted deprotection of methylenedi-
oxy bridge in product (+)-13 was not very clean, the desired
natural product (+)-artabotriolcaffeate (15) was obtained in
~5% yield. Plausibly the free vicinal diol system in com-
pound (+)-13/(+)-15 was responsible for the noticed exces-
sive decomposition. However, the alternatively performed
EDCI-prompted dehydrative coupling of (+)-allylic alcohol 6
with the double OMOM protected caffeaic acid delivered
Stereochemical assignments are based on the optical rotation of the
known compounds. Melting points are uncorrected. The1H NMR
spectra were recorded on 200 MHz, 400 MHz, or 500 MHz NMR spec-
trometer using TMS as an internal standard. The 13C NMR spectra
were recorded on 200 (50 MHz), 400 (100 MHz), or 500 (125 MHz)
NMR spectrometer. Mass spectra were taken on MS-TOF mass spec-
trometer. HRMS (ESI) were taken on Orbitrap (quadrupole plus ion
trap) and TOF mass analyzer. The IR spectra were recorded on an FT-
IR spectrometer. Column chromatographic separations were carried
out on silica gel (60–120 mesh). Commercially available TBDMSCl,
O
O
OH
OH
O
O
O
O
p-TSA, MeOH, 0 °C
O
HO
O
O
O
O
O
EDCI, Et3N, CH2Cl2
reflux, 6 h (84%)
O
5 h (81%)
(+)-13
(+)-12
O
O
OH
BBr3, CH2Cl2, –78 to
25 °C, 2 h (5%)
(+)-6
O
MOMO
OH
OH
O
O
O
O
p-TSA, MeOH
HO
OH
OH
MOMO
O
O
OMOM
0 °C, 3 h (67%)
EDCI, Et3N, CH2Cl2
reflux, 6 h (82%)
OMOM
(+)-Artabotriolcaffeate (15)
(+)-14
Scheme 3 Synthesis of (+)-artabotriolcaffeate
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
R. U. Batwal, N. P. Argade
Paper
Synthesis
DIBAL, EDCI, DMAP, TBAF solution in THF (1.0 M), dimethoxypropane,
cinnamic acid, Boc-protected diamines were used. Amano PS enzyme
from Sigma-Aldrich was used.
resulting residue using EtOAc–PE (1:19) as an eluent afforded the
pure product (–)-3 as a viscous oil; yield: 1.09 g (94%); [α]D25 –20.9 (c
0.40 EtOH).
IR (CHCl3): 1759, 1736, 1686 cm–1
.
Amano PS-Catalyzed Resolution of Dimethyl (±)-2-Hydroxy-3-
methylenesuccinate [(±)-1]
1H NMR (CDCl3, 200 MHz): δ = 0.10 (s, 3 H), 0.13 (s, 3 H), 0.91 (s, 9 H),
3.72 (s, 3 H), 3.78 (s, 3 H), 5.08 (dd, J = 2, 2 Hz, 1 H), 6.07 (dd, J = 2, 2
Hz, 1 H), 6.38 (dd, J = 2, 2 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): δ = –5.4, –5.2, 18.3, 25.6, 52.0, 52.3, 70.9,
126.4, 138.7, 165.9, 171.2.
To a stirred solution of dimethyl (±)-2-hydroxy-3-methylenesuccinate
(1; 2.00 g, 9.25 mmol) and vinyl acetate (3.98 g, 46.25 mmol) in ace-
tone (25 mL) was added the enzyme Amano PS (100 mg, Sigma-Al-
drich). The resulting reaction mixture was stirred at 25 °C for 72 h
with monitoring of the reaction progress by HPLC. The reaction mix-
ture was filtered through a Celite bed and washed with EtOAc (30
mL). Concentration of organic layer in vacuo, followed by silica gel
(60–120 mesh) column chromatographic purification of the resulting
residue using EtOAc–PE (1:3) as an eluent afforded the pure product
(–)-1 as a viscous oil;8a yield: 920 mg (46%) and (+)-2 as a viscous
oil;8a yield: 1.36 g (54%).
MS (ESI): m/z = 289 [M + H]+, 311 [M + Na]+.
(+)-(S)-2-[(tert-Butyldimethylsilyl)oxy]-3-methylenebutane-1,4-
diol [(+)-4]
To a stirred solution of diester (–)-3 (1.00 g, 3.46 mmol) in THF (10
mL) was added DIBAL solution (0.16 mL, 0.16 mmol, 1 M in hexane) in
dropwise fashion at –78 °C and the reaction mixture was stirred un-
der argon atmosphere for 2 h. The reaction was quenched with sat. aq
NH4Cl and the reaction mass was concentrated in vacuo. The obtained
residue was diluted with EtOAc (20 mL) and the organic layer was
washed with brine (15 mL) and dried (Na2SO4). Concentration of or-
ganic layer in vacuo, followed by silica gel (60–120 mesh) column
chromatographic purification of the resulting residue using EtOAc–PE
(2:3) as an eluent afforded the pure product (+)-4 as a viscous oil;
yield: 580 mg (72%); [α]D25 +6.3 (c 0.50 EtOH).
(–)-1
[α]D25 –18.5 (c 0.30 EtOH, 98% ee).
IR (CHCl3): 3503, 1746, 1726, 1636 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 3.58 (br s, 1 H), 3.79 (s, 6 H), 4.88 (br s,
1 H), 5.97 (s, 1 H), 6.39 (s, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 52.1, 53.0, 71.2, 129.2, 137.8, 165.6,
IR (CHCl3): 3456, 1652 cm–1
.
172.7.
MS (ESI): m/z =175 [M + H]+, 197 [M + Na]+.
1H NMR (CDCl3, 200 MHz): δ = 0.07 (s, 3 H), 0.10 (s, 3 H), 0.91 (s, 9 H),
2.46 (br s, 2 H), 3.54–3.70 (m, 2 H), 4.10 (d, J = 12 Hz, 1 H), 4.21 (d, J =
12 Hz, 1 H), 4.34 (t, J = 6 Hz, 1 H), 5.18 (br s, 1 H), 5.20 (br s, 1 H).
(+)-2
[α]D25 +48.6 (c 0.19 EtOH, 94% ee).
13C NMR (CDCl3, 50 MHz): δ = –5.1, –4.8, 18.1, 25.7, 63.1, 66.5, 75.2,
IR (CHCl3): 1755, 1747, 1732, 1638 cm–1
.
114.2, 148.1.
MS (ESI): m/z = 255 [M + Na]+.
1H NMR (CDCl3, 200 MHz): δ = 2.18 (s, 3 H), 3.77 (s, 3 H), 3.82 (s, 3 H),
HRMS (ESI): m/z [M + Na]+ calcd for C11H24O3NaSi: 255.1392; found:
6.00 (s, 1 H), 6.02 (s, 1 H), 6.51 (s, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 20.6, 52.4, 52.7, 70.2, 130.7, 134.7,
255.1383.
164.8, 168.3, 169.7.
(+)-(S)-3-Methylenebutane-1,2,4-triol [(+)-Artabotriol, (+)-5]
MS (ESI): m/z = 217 [M + H]+, 239 [M + Na]+, 255 [M + K]+.
To a stirred solution of diol (+)-4 (550 mg, 2.36 mmol) in anhyd THF
(10 mL) was added slowly a solution of Bu4NF (2.60 mL, 2.60 mmol, 1
M in THF) at 0 °C and the reaction mixture was stirred for 10 h at 25
°C. The reaction was quenched with sat. aq NH4Cl and the mixture
was concentrated in vacuo. The obtained residue was diluted with
EtOAc (20 mL) and the organic layer was washed with brine (20 mL)
and dried (Na2SO4). Concentration of organic layer in vacuo, followed
by silica gel (60–120) column chromatographic purification of the re-
sulting residue using MeOH–EtOAc (1:19) as an eluent afforded the
pure product (+)-5 as a viscous oil; yield: 260 mg (93%); [α]D25 +4.5 (c
0.28 MeOH).
Dimethyl (S)-(+)-2-Hydroxy-3-methylenesuccinate [(+)-1]
To a stirred solution of acetate (+)-2 (1.20 g, 5.55 mmol) in MeOH (10
mL) was added aq 2 N HCl (5 mL) at 0 °C and the reaction mixture was
stirred for 2 h. The mixture was concentrated in vacuo and the ob-
tained residue was diluted with EtOAc (20 mL). The organic layer was
washed with H2O (15 mL), brine (15 mL), and dried (Na2SO4). Concen-
tration of organic layer in vacuo, followed by silica gel (60–120) col-
umn chromatographic purification of the resulting residue using
EtOAc–PE (1:3) as an eluent afforded the pure product (+)-1 as a vis-
cous oil; yield: 760 mg (90%); [α]D25 +18.0 (c 0.28 EtOH). The obtained
spectroscopic data were identical with the data for (–)-1.
IR (CHCl3): 3355 cm–1
.
1H NMR (200 MHz, acetone-d6): δ = 3.40–4.35 (m, 8 H), 5.13 (s, 2 H).
13C NMR (50 MHz, acetone-d6): δ = 64.2, 68.0, 75.7, 112.0, 152.2.
Dimethyl (S)- (–)-2-[(tert-Butyldimethylsilyl)oxy]-3-methylene-
succinate [(–)-3]
To a stirred solution of alcohol (+)-1 (700 mg, 4.02 mmol) in CH2Cl2
(20 mL) were added imidazole (301 mg, 4.42 mmol) and TBDMSCl
(666 mg, 4.42 mmol) at 0 °C under argon atmosphere. The reaction
mixture was stirred at 25 °C for 6 h. The mixture was concentrated in
vacuo and the obtained residue was diluted with EtOAc (40 mL). The
organic layer was washed with H2O (30 mL) and brine (30 mL), and
dried (Na2SO4). Concentration of organic layer in vacuo, followed by
silica gel (60–120 mesh) column chromatographic purification of the
(+)-(S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)prop-2-en-1-ol [(+)-6]
To a stirred solution of triol (+)-5 (250 mg, 2.11 mmol) in anhyd THF
(5 mL) was added 2,2-dimethoxypropane (242 mg, 2.33 mmol) at 0 °C
and the reaction mixture was stirred for 4 h at 25 °C. The mixture was
concentrated in vacuo and the obtained residue was diluted with
EtOAc (20 mL). The organic layer was washed with H2O (20 mL) and
brine (15 mL), and dried (Na2SO4). Concentration of organic layer in
vacuo, followed by silica gel (60–120) column chromatographic puri-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
R. U. Batwal, N. P. Argade
Paper
Synthesis
fication of the resulting residue using EtOAc–PE (1:4) as an eluent af-
forded the pure product (+)-6 as a viscous oil; yield: 284 mg (85%);
[α]D25 +35.9 (c 0.30 CHCl3).
HRMS (ESI): m/z [M + Na]+ calcd for C21H28N2O4Na: 395.1941; found:
395.1933.
IR (CHCl3): 3419, 1656 cm–1
.
(+)-(S)-N-(4-Cinnamamidobutyl)-3,4-dihydroxy-2-methylenebu-
tanamide [(+)-Grandiamide D, (+)-9]
1H NMR (200 MHz, CDCl3): δ = 1.40 (s, 3 H), 1.46 (s, 3 H), 2.25 (br s, 1
H), 3.72 (t, J = 8 Hz, 1 H), 4.05–4.30 (m, 3 H), 4.68 (t, J = 8 Hz, 1 H), 5.21
(s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 25.4, 26.3, 63.3, 68.9, 77.7, 109.4,
113.4, 145.7.
To a stirred solution of (+)-8 (50 mg, 0.13 mmol) in anhyd MeOH (2
mL) was added a catalytic amount of p-TSA (5 mg) at 0 °C under argon
atmosphere and the reaction mixture was stirred for 2 h. The mixture
was concentrated in vacuo and the obtained residue was diluted with
EtOAc (10 mL). The organic layer was washed with brine (10 mL) and
dried (Na2SO4). Concentration of organic layer in vacuo, followed by
silica gel (60–120) column chromatographic purification of the re-
sulting residue using MeOH–EtOAc (1:19) as an eluent afforded the
pure product (+)-9 as a white solid; yield: 34 mg (77%); mp 105–107
(+)-(S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)acrylic Acid [(+)-7]
To a stirred solution of (+)-6 (100 mg, 0.63 mmol) in CH2Cl2 (2 mL)
was added active MnO2 (1.37 g, 15.75 mmol) at 25 °C and the reaction
mixture was stirred for 36 h. The inorganic materials from the mix-
ture were filtered off through a Celite bed, which was thoroughly
washed with CH2Cl2 (10 mL). The combined filtrates were evaporated
to give the crude α,β-unsaturated aldehyde, which was used in the
next step without any purification. A suspension of Ag2O prepared
from AgNO3 (115 mg, 0.69 mmol) and NaOH (100 mg, 2.52 mmol) in
H2O (3 mL) was added to the above crude aldehyde at 0 °C and the
reaction mixture was stirred at 25 °C for 1 h. The mixture was filtered
through a Celite bed and the filtrate was acidified with sat. aq oxalic
acid followed by extraction with EtOAc. Concentration of organic lay-
er in vacuo, followed by silica gel (60–120) column chromatographic
purification of the resulting residue using EtOAc–PE (2:3) as an eluent
afforded the pure product (+)-7 as a white solid; yield: 74 mg (68%);
25
25
°C; [α]D +2.7 (c 0.60 MeOH, 98% ee) {Lit.5 [α]D +4.76 (c 0.50
MeOH)}.
IR (CHCl3): 3374, 1658, 1607 cm–1
.
1H NMR (200 MHz, CD3OD): δ = 1.61 (br s, 4 H), 3.20–3.40 (m, 4 H),
3.49 (dd, J = 11, 8 Hz, 1 H), 3.65 (dd, J = 10, 4 Hz, 1 H) 4.53 (t, J = 6 Hz,
1 H), 5.63 (s, 1 H), 5.80 (s, 1 H), 6.61 (d, J = 16 Hz, 1 H), 7.30–7.45 (m, 3
H), 7.45–7.60 (m, 3 H).
13C NMR (100 MHz, CD3OD): δ = 27.8, 27.9, 40.0, 40.2, 66.7, 73.3,
119.9, 121.9, 128.8, 129.9, 130.8, 136.3, 141.60, 146.3, 168.6, 170.4.
MS (ESI): m/z = 355 [M + Na]+.
(+)-(S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)allyl (E)-3-(Ben-
zo[d][1,3]dioxol-5-yl)acrylate [(+)-12]
mp 60–62 °C; [α]D +37.2 (c 0.60 CHCl3) {Lit.9 [α]D +47.3 (c 1.12
25
25
CHCl3)}.
To a stirred solution of 3,4-(methylenedioxy)cinnamic acid (100 mg,
0.52 mmol) in CH2Cl2 (10 mL) were added alcohol (+)-6 (74 mg, 0.47
mmol), EDCI (97 mg, 0.52 mmol), Et3N (105 mg, 1.04 mmol), and a
catalytic amount of DMAP at 0 °C under argon atmosphere. The reac-
tion mixture was allowed to gradually reach to 25 °C and further re-
fluxed for 6 h. The reaction was quenched with H2O (10 mL) and the
mixture was extracted with CH2Cl2 (2 × 10 mL). The combined organic
layers were washed with brine (10 mL) and dried (Na2SO4). Concen-
tration of organic layer in vacuo, followed by silica gel (60–120) col-
umn chromatographic purification of the resulting residue using
EtOAc–PE (1:3) as an eluent afforded the pure product (+)-12 as a vis-
cous oil; yield: 176 mg (84%); [α]D25 +28.6 (c 0.64 CHCl3).
IR (CHCl3): 3684, 3620, 1701, 1633 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.44 (s, 3 H), 1.47 (s, 3 H), 3.65 (t, J = 10
Hz, 1 H), 4.38 (t, J = 10 Hz, 1 H), 4.87 (t, J = 10 Hz, 1 H), 6.18 (s, 1 H),
6.45 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 25.5, 26.3, 70.1, 73.8, 109.6, 127.1,
138.7, 170.7.
(+)-(S)-N-(4-Cinnamamidobutyl)-2-(2,2-dimethyl-1,3-dioxolan-4-
yl)acrylamide [(+)-8]
To a stirred solution of acid (+)-7 (40 mg, 0.23 mmol) in CH2Cl2 (5 mL)
were added amine (56 mg, 0.25 mmol), EDCI (48 mg, 0.25 mmol),
Et3N (25 mg, 0.25 mmol), and a catalytic amount of DMAP at 0 °C un-
der argon atmosphere. The reaction mixture was allowed to reach 25
°C and stirred for 4 h. The reaction was quenched with H2O (5 mL)
and the mixture was extracted with CH2Cl2 (2 × 10 mL). The combined
organic layers were washed with brine (10 mL) and dried (Na2SO4).
Concentration of organic layer in vacuo, followed by silica gel (60–
120) column chromatographic purification of the resulting residue
using EtOAc as an eluent afforded the pure product (+)-8 as a white
solid; yield: 75 mg (87%); mp 110–112 °C; [α]D25 +15.3 (c 0.20 CHCl3).
IR (CHCl3): 1708, 1632, 1608 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.41 (s, 3 H), 1.46 (s, 3 H), 3.77 (t, J = 8
Hz, 1 H), 4.19 (t, J = 8 Hz, 1 H), 4.64 (t, J = 8 Hz, 1 H), 4.75 (dd, J = 20, 16
Hz, 2 H), 5.28 (s, 1 H), 5.39 (s, 1 H), 6.01 (s, 2 H) 6.28 (d, J = 16 Hz, 1 H),
6.82 (d, J = 12 Hz, 1 H), 7.01 (d, J = 8 Hz, 1 H), 7.04 (s, 1 H), 7.61 (d, J =
16 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.6, 26.2, 64.0, 69.1, 77.1, 101.6,
106.5, 108.5, 109.4, 114.8, 115.4, 124.6, 128.6, 141.6, 145.0, 148.3,
149.7, 166.6.
IR (CHCl3): 3688, 3621, 1732, 1663, 1623 cm–1
.
MS (ESI): m/z= 355 [M + Na]+.
1H NMR (500 MHz, CDCl3): δ = 1.42 (s, 3 H), 1.48 (s, 3 H), 1.63 (s, 2 H),
1.80 (s, 2 H), 3.37 (d, J = 5 Hz, 2 H), 3.43 (d, J = 5 Hz, 2 H), 3.75 (t, J = 10
Hz, 1 H), 4.29 (t, J = 10 Hz, 1 H), 4.86 (t, J = 10 Hz, 1 H), 5.70 (s, 1 H),
5.93 (s, 1 H), 6.20 (br s, 1 H), 6.43 (d, J = 20 Hz, 1 H), 6.80 (br s, 1 H),
7.36 (s, 3 H), 7.50 (d, J = 5 Hz, 2 H), 7.62 (d, J = 15 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 25.2, 26.4, 26.8, 27.0, 39.0, 39.2, 69.4,
75.6, 109.6, 120.6, 120.7, 127.7, 128.8, 129.6, 134.8, 140.9, 141.8,
166.1, 166.6.
HRMS (ESI): m/z [M + Na]+ calcd for C18H20O6Na: 355.1152; found:
355.1142.
(+)-(S)-3,4-Dihydroxy-2-methylenebutyl (E)-3-(Benzo[d][1,3]diox-
ol-5-yl)acrylate [(+)-13]
To a stirred solution of (+)-12 (50 mg, 0.15 mmol) in anhyd MeOH (5
mL) was added a catalytic amount of p-TSA (5 mg) at 0 °C under argon
atmosphere and the reaction mixture was stirred for 5 h. The mixture
was concentrated in vacuo and the obtained residue was diluted with
EtOAc (10 mL). The organic layer was washed with brine (10 mL) and
MS (ESI): m/z = 395 [M + Na]+.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
R. U. Batwal, N. P. Argade
Paper
Synthesis
dried (Na2SO4). Concentration of organic layer in vacuo, followed by
silica gel (60–120) column chromatographic purification of the re-
sulting residue using EtOAc–PE (3:2) as an eluent afforded the pure
product (+)-13 as a viscous oil; yield: 36 mg (81%); [α]D25 +3.7 (c 0.90
CHCl3).
Method B: To a stirred solution of (+)-14 (100 mg, 0.24 mmol) in an-
hyd MeOH (5 mL) were added a catalytic amount of p-TSA (5 mg) at 0
°C under argon atmosphere. The reaction mixture was stirred for 3 h.
The mixture was concentrated in vacuo and the obtained residue was
diluted with EtOAc (10 mL). The organic layer was washed with brine
(5 mL) and dried (Na2SO4). Concentration of organic layer in vacuo,
followed by silica gel (60–120) column chromatographic purification
of the resulting residue using EtOAc as an eluent afforded the pure
product (+)-15 as a white solid; yield: 46 mg (67%); mp 168–169 °C;
[α]D25 +1.2 (c 0.80 MeOH) {Lit.4a [α]D25 +2.3 (c 0.13 MeOH)}.
IR (CHCl3): 3390, 1700, 1629, 1606 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 2.47 (br s, 1 H), 2.89 (br s, 1 H), 3.67
(dd, J = 12, 6 Hz, 1 H), 3.79 (dd, J = 12, 4 Hz, 1 H), 4.36 (dd, J = 6, 4 Hz, 1
H), 4.75 (s, 2 H), 5.32 (s, 1 H), 5.36 (s, 1 H), 6.01 (s, 2 H), 6.28 (d, J = 16
Hz, 1 H), 6.82 (d, J = 10 Hz, 1 H), 7.01 (d, J = 8 Hz, 1 H), 7.03 (s, 1 H),
7.62 (d, J = 16 Hz, 1 H).
IR (CHCl3): 3383, 1690, 1602 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 3.35–3.50 (m, 2 H), 4.07 (q, J = 4 Hz,
1 H), 4.64 (t, J = 4 Hz, 1 H), 4.68 (s, 2 H), 5.01 (d, J = 8 Hz, 1 H), 5.11 (s,
1 H), 5.18 (s, 1 H), 6.30 (d, J = 16 Hz, 1 H), 6.77 (d, J = 8 Hz, 1 H), 7.02
(dd, J = 8, 4 Hz, 1 H), 7.07 (d, J = 4 Hz, 1 H), 7.50 (d, J = 16 Hz, 1 H), 9.15
(s, 1 H), 9.61 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 64.3, 65.6, 73.2, 101.6, 106.5, 108.5,
115.2, 115.4, 124.7, 128.5, 143.3, 145.4, 148.3, 149.8, 167.0.
MS (ESI): m/z = 315 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C15H16O6Na: 315.0839; found:
315.0833.
13C NMR (100 MHz, DMSO-d6): δ = 63.6, 65.3, 72.8, 112.0, 113.8,
114.9, 115.8, 121.5, 125.5, 145.4, 145.5, 145.6, 148.5, 166.2.
MS (ESI): m/z = 303 [M + Na]+.
(+)-(S)-2-(2,2-Dimethyl-1,3-dioxolan-4-yl)allyl (E)-3-[3,4-Bis(me-
thoxymethoxy)phenyl]acrylate [(+)-14]
To a stirred solution of (E)-3-[3,4-bis(methoxymethoxy)phenyl]acryl-
ic acid (100 mg, 0.37 mmol) in CH2Cl2 (10 mL) were added alcohol (+)-
6 (52 mg, 0.33 mmol), EDCI (71 mg, 0.37 mmol), Et3N (75 mg, 0.74
mmol) and a catalytic amount of DMAP at 0 °C under argon atmo-
sphere. The reaction mixture was allowed to reach to 25 °C and fur-
ther refluxed for 6 h. The reaction was quenched with H2O (10 mL)
and the mixture was extracted with CH2Cl2 (2 × 10 mL). The combined
organic layers were washed with brine (10 mL) and dried (Na2SO4).
Concentration of organic layer in vacuo, followed by silica gel (60–
120) column chromatographic purification of the resulting residue
using EtOAc–PE (2:5) as an eluent afforded the pure product (+)-14 as
a viscous oil; yield: 176 mg (84%); [α]D25 +7.5 (c 0.52, MeOH).
Acknowledgment
R.U.B. thanks UGC, New Delhi, for the award of a research fellowship.
N.P.A. thanks Department of Science and Technology, New Delhi, for
the financial support. We also gratefully acknowledge the financial
support from CSIR-Network Project. We thank Mrs. S. S. Kunte from
NCL, Pune, for the HPLC data.
Supporting Information
1H NMR, 13C NMR and DEPT spectra of compounds 1–9 and 12–15 as
well as HPLC data for the enantiomeric purity of the compounds 1, 2,
IR (CHCl3): 3685, 3618, 1710, 1635, 1601 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 1.41 (s, 3 H), 1.46 (s, 3 H), 3.52 (s, 3 H),
3.53 (s, 3 H), 3.77 (t, J = 8 Hz, 1 H), 4.19 (t, J = 8 Hz, 1 H), 4.65 (t, J = 8
Hz, 1 H), 4.75 (s, 2 H), 5.26 (s, 2 H), 5.27 (s, 2 H), 5.29 (s, 1 H), 5.39 (s, 1
H), 6.34 (d, J = 16 Hz, 1 H), 7.16 (s, 2 H), 7.37 (s, 1 H) 7.63 (d, J = 16 Hz,
1 H).
13C NMR (125 MHz, CDCl3): δ = 25.6, 26.3, 56.30, 56.32, 64.0, 69.1,
77.0, 95.1, 95.5, 109.5, 114.9, 115.7, 116.1, 116.2, 123.6, 128.8, 141.7,
144.9, 147.4, 149.3, 166.6.
and
9
are
available
free
of
charge
online
at
http://dx.doi.org/10.1055/s-0035-1561588.
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References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G