Total synthesis of 6- o -benzoylzeylenol from diacetone glucose

Article abstract of DOI:10.1055/s-0033-1340903

A total synthesis of 6-O-benzoylzeylenol from diacetone glucose is described. The key steps were a crossed aldol-Cannizzaro reaction to create a quaternary carbon stereocenter, and cyclization through ring closure metathesis (RCM). Of the four stereogenic centers, two were derived from diacetone glucose, the quaternary stereocenter was created by means of the crossed aldol-Cannizzaro reaction, and the fourth stereogenic center was produced by a Sharpless asymmetric epoxidation. Finally, cyclization through RCM and deprotection by removal of a benzyl group with titanium(IV) chloride gave the target molecule. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340903

1532▌
PAPER
paper
Total Synthesis of 6-O-Benzoylzeylenol from Diacetone Glucose
6-O-Benzoylzeylenol
Post Sai Reddy,* Gangavaram V. M. Sharma
Organic and Biomolecular Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
E-mail: saireddypost@gmail.com; Fax +91(40)27160757
Received: 27.11.2013; Accepted after revision: 13.02.2014
tection and benzoylation. Diene 4 might be derived from
alcohol 5, which in turn might be obtained from alcohol 6.
The known alcohol 67 can be prepared from diacetone glu-
cose [DAG (7); 1,2:5,6-di-O-isopropylidene-α-D-gluco-
Abstract: A total synthesis of 6-O-benzoylzeylenol from diacetone
glucose is described. The key steps were a crossed aldol–Cannizzaro
reaction to create a quaternary carbon stereocenter, and cyclization
through ring closure metathesis (RCM). Of the four stereogenic
centers, two were derived from diacetone glucose, the quaternary furanose].
stereocenter was created by means of the crossed aldol–Cannizzaro
reaction, and the fourth stereogenic center was produced by a
Sharpless asymmetric epoxidation. Finally, cyclization through
MOMO
HO
HO
OBz
OH
RCM and deprotection by removal of a benzyl group with titani-
MOMO
OBn
OH
BzO
O
um(IV) chloride gave the target molecule.
HO
O
Key words: ring closure, metathesis, aldol reactions, Cannizzaro
reactions, stereoselective synthesis
MOMO
OBz
O
BnO
O
2
4
5
O
Zeylenols are polyoxygenated cyclohexene natural prod-
HO
TBSO
O
O
O
ucts that have been isolated from various sources. (+)-
Zeylenol (1; Figure 1)1–5 was first isolated in 1987 by
Tuntiwachwuttikul and co-workers from a natural source,
initially described as a member of the genus Bosenber-
gia,1a but subsequently identified, in 1989, as a species of
Kaempferia.1b (+)-Zeylenol (1) showed selective cytotox-
icity towards HL-60 leukemia cells.1c The related com-
pounds 6-O-benzoylzeylenol (2)1b and uvaribonol A (3)1b
also were isolated from the same Kaempferia species.
O
O
BnO
O
HO
DAG (7)
6
Scheme 1 Retrosynthetic analysis for 6-O-benzoylzeylenol (2)
Accordingly, the aldehyde 7a7a derived from DAG (7) un-
derwent a crossed aldol–Cannizzaro reaction with 37%
aqueous formaldehyde in the presence of 1 M aqueous so-
dium hydroxide in a 1:1 mixture of tetrahydrofuran and
water at room temperature for 16 hours to give the 1,3-
diol 7b7a in 78% yield (Scheme 2). Selective protection of
diol 7b with tert-butyl(chloro)dimethylsilane and imidaz-
ole at –20 °C for one hour gave the known alcohol 67b,7c in
58% yield. Treatment of alcohol 6 with chloro(meth-
BzO
HO
BzO
HO
HO
HO
HO
OH
BzO
2
OH
BzO
OH
1
6
3
OBz
OBz
OBz
2
3
1
oxy)methane
(MOMCl),
diisopropyl(ethyl)amine
Figure 1 Structures of (+)-zeylenol (1) and its congeners 6-O-ben-
zoylzeylenol (2) and uvaribonol A (3)
(DIPEA), and 4-(N,N-dimethylamino)pyridine (DMAP)
in dichloromethane at 0 °C to room temperature for eight
hours gave the protected compound 8 in 92% yield
(Scheme 2). Desilylation of 8 by treatment with tetrabu-
tylammonium fluoride in tetrahydrofuran at 0 °C to room
temperature for four hours gave alcohol 9 (82%). Oxida-
tion under Swern conditions using oxalyl dichloride, di-
methyl sulfoxide, and triethylamine in dichloromethane
gave aldehyde 10. Treatment of 10 with vinylmagnesium
bromide in tetrahydrofuran at 0 °C to room temperature
for 20 minutes gave the diastereomeric allylic alcohols 5
and ent-5 as an inseparable mixture (~1:5 ratio) in 76%
yield.
6-O-Benzoylzeylenol (2) is an attractive synthetic target
by virtue of its interesting structural features, including a
chiral quaternary carbon center, five hydroxy/alkoxy
groups, and a double bond in a six-carbon system, besides
its biological activities. Recently, Palframan et al.6 report-
ed a total synthesis of (+)-zeylenol (1) and its congeners 2
and 3 by photooxygenation of a microbial arene oxidation
product.
The retrosynthetic analysis of 6-O-benzoylzeylenol (2) is
shown in Scheme 1. The synthesis of 2 might be achieved
by ring closure metathesis of diene 4, followed by depro-
An alternative synthesis of segment 5 was achieved by an
asymmetric approach. Wittig olefination of aldehyde 10
with ethyl (triphenylphosphoranylidene)acetate in
CH2Cl2 at 0 °C to room temperature for two hours gave
the α,β-unsaturated ester 11 exclusively in 88% yield
SYNTHESIS 2014, 46, 1532–1538
Advanced online publication: 27.03.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340903; Art ID: SS-2013-Z0764-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
6-O-Benzoylzeylenol
1533
O
temperature for 20 minutes gave the corresponding iodo
compounds 13b and 14b, which on reaction with zinc and
sodium iodide in refluxing methanol gave the allylic alco-
hols 5 (86%) and ent-5 (72%), respectively. The product
obtained from (+)-DIPT corresponded to the minor allylic
alcohol 5, whereas the product from (–)-DIPT corre-
sponded to ent-5 obtained by the Grignard reaction.
HO
HO
O
O
H
O
O
a
DAG (7)
O
O
BnO
BnO
BnO
7a
7b
HO
MOMO
RO
O
O
b
O
O
c, d
TBSO
Treatment of alcohol 5 with MOMCl, DIPEA, and DMAP
in dichloromethane at 0 °C to room temperature for 12
hours gave the methoxymethyl ether 15 in 78% yield
(Scheme 4). Acid-mediated hydrolysis of ether 15 with
70% aqueous acetic acid at 55 °C for eight hours gave the
lactol 16 (63%) along with traces of triol 17. Wittig
olefination8 of lactol 16 with methyl(triphenyl)phospho-
nium bromide and butyllithium in tetrahydrofuran at 0 °C
to room temperature for two hours gave the diene 4 in
65% yield. RCM9,10 of diene 4 with the Grubbs second-
generation catalyst in toluene at room temperature for two
hours gave the olefin 18 in 76% yield. Treatment of olefin
18 with benzoyl chloride and pyridine in dichloromethane
at 0 °C to room temperature for eight hours gave benzoate
19 (85%), which on deprotection of the methoxymethyl
groups by using trifluoroacetic acid in dichloromethane at
0 °C to room temperature for two hours gave triol 20 in
70% yield (Scheme 4). Triol 20 reacted with benzoyl
chloride and pyridine in dichloromethane at 0 °C to room
temperature for four hours to give the tribenzoate 21 in
81% yield.
O
O
BnO
6
8 R = TBS
9 R = OH
MOMO
O
O
HO
O
O
e
f
O
MOMO
O
BnO
O
BnO
5 + ent-5 (1:5 ratio)
10
Scheme 2 Synthesis of segment 5. Reagents and conditions: (a) 37%
aq HCHO, THF, H2O, 1 M aq NaOH, 0 °C to r.t, 16 h, 78%;
(b) TBSCl, imidazole, CH2Cl2, –20 °C, 1 h, 58%; (c) MOMCl,
DIPEA, DMAP, CH2Cl2, 0 °C to r.t., 8 h, 92%; (d) TBAF, THF, 0 °C
to r.t., 4 h, 82%; (e) (ClCO)2, DMSO, Et3N, CH2Cl2, –78 °C, 2 h; (f)
CH2=CHMgBr, THF, 0 °C to r.t., 20 min, 76%.
(Scheme 3). Reduction of 11 with diisobutylaluminum
hydride in dichloromethane at 0 °C to room temperature
for 30 minutes gave allylic alcohol 12 (70%), which was
independently subjected to Sharpless asymmetric epoxi-
dation with cumene hydroperoxide (CHP) and diisopro-
pyl (+)-tartrate [(+)-DIPT] or (–)-DIPT in anhydrous
dichloromethane at –20 °C for 14 hours (Scheme 3) to
give the epoxy alcohols 13a (86%) and 14a (90%), re-
spectively. Treatment of 13a and 14a separately with tri-
phenylphosphine, diiodine, and imidazole at 0 °C to room
Finally, treatment of tribenzoate 21 with titanium(IV)
chloride in dichloromethane at 0 °C to room temperature
for two hours gave the target molecule 2 in 71% yield
(Scheme 4). The optical rotation of the synthetic 2 agreed
MOMO
MOMO
O
O
O
O
HO
MOMO
MOMO
a
b
O
O
a
c
O
O
b
10
MOMO
EtO
O
O
O
HO
O
BnO
BnO
BnO
15
BnO
12
O
5
11
OH
O
MOMO
MOMO
RO
MOMO
R
OH
O
O
d, e
O
HO
O
f
O
c, e
MOMO
MOMO
OH
OH
BnO
BnO
O
BnO
O
BnO
4
16 R = MOM (63%)
17 R = H (trace)
13a R = OH
13b R = I
5 (86%)
12
RO
MOMO
HO
MOMO
R
O
O
O
HO
HO
O
d, e
f
O
RO
OBn
OBz
f, e
MOMO
OBn
OR
g
MOMO
2
O
BnO
O
ent-5 (72%)
BnO
14a R = OH
14b R = I
20 R = H
21 R = Bz (81%)
18 R = H
19 R = Bz (85%)
Scheme 3 Synthesis of segment 5. Reagents and conditions: (a)
Ph3P=CHCO2Et, CH2Cl2, 0 °C to r.t., 2 h, 88%; (b) DIBAL-H,
CH2Cl2, 0 °C to r.t., 30 min, 70%; (c) (+)-DIPT, Ti(i-PrO)4, CHP,
CH2Cl2, powdered 4 Å MS, –20 °C, 14 h, 86%; (d) (–)-DIPT, Ti(i-
PrO)4, CHP, CH2Cl2, powdered 4 Å MS, –20 °C, 14 h, 90%; (e) I2,
Ph3P, imidazole, THF, 0 °C to r.t., 20 min; (f) Zn, NaI, MeOH, reflux,
12 h.
Scheme 4 Synthesis of target molecule 2. Reagents and conditions:
(a) MOMCl, DIPEA, DMAP, CH2Cl2, 0 °C to r.t., 12 h, 78%; (b) 70%
aq AcOH, 55 °C, 8 h; (c) Ph3P+MeBr–, n-BuLi, THF, 0 °C to r.t., 2 h,
65%; (d) Grubbs II catalyst, toluene, r.t., 2 h, 76%; (e) BzCl, py,
CH2Cl2, 0 °C to r.t., 8 h; (f) TFA, CH2Cl2, 0 °C to r.t., 2 h, 70%; (g)
TiCl4, CH2Cl2, 0 °C to r.t., 2 h, 71%.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1532–1538

1534
P. S. Reddy, G. V. M. Sharma
PAPER
13C NMR (75 MHz, CDCl3): δ = 137.6, 128.4 (2 C), 127.7, 127.5 (2
C), 112.7, 105.1, 96.8, 89.2, 86.1, 84.2, 72.3, 67.3, 63.1, 55.2, 27.3,
26.8, 25.9 (3 C), 18.2, –5.4, –5.5.
HRMS (ESI+): m/z [M + Na]+ calcd for C24H40NaO7Si: 491.24355;
found: 491.24300.
well with that of the natural product {[α]D22 –58.1 (c 0.12,
CHCl3); Lit.1b [α]D22 –59.7 (c 0.39, CHCl3)}.
Thus, a synthesis of 2 from diacetone glucose (7) was
achieved in which the quaternary carbon center was creat-
ed by a crossed aldol–Cannizzaro reaction, and the cyclo-
hexene ring core was formed by an efficient RCM
reaction.
3-O-Benzyl-4-[(methoxymethoxy)methyl]-1,2-O-(1-methyleth-
ylidene)-β-L-arabinofuranose (9)
A 1 M solution of TBAF in THF (18.80 mL) was added to a solution
of furanose 8 (8.0 g, 17.09 mmol) in THF (16 mL) at 0 °C, and the
mixture was stirred at r.t. for 4 h. THF was removed under reduced
pressure and the residue was purified by column chromatography
(silica gel, 20% EtOAc–PE) to give a colorless syrup; yield: 4.96
(82%); [α]D27 –34.9 (c 0.22, CHCl3).
Crude products were purified by column chromatography on 60–
120 mesh silica gel. 1H NMR spectra were recorded at 300 and 500
MHz, and 13C NMR spectra were recorded at 50 and 75 MHz on
Bruker Avance 300 and Varian Inova 500 spectrometers. NMR
spectra (1H and 13C) were recorded in CDCl3 and chemical shifts are
reported with respect to internal TMS as a reference. FTIR spectra
were measured with a Thermo Nicolet Nexus 670 spectrometer.
Optical rotations were measured with a JASCO DIP 300 digital po-
larimeter. Mass spectra were recorded with a Finnigan MAT 1210
double-focusing mass spectrometer operating with a direct inlet
system.
IR (CHCl3): 3480, 3031, 2987, 2935, 1456, 1379, 1246, 1213, 1150,
1110, 1045, 917, 864, 739, 700 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.41–7.27 (m, 5 H, Ar-H), 5.97 (d,
J = 4.5 Hz, 1 H, C-1 H), 4.77 (dd, J = 2.0, 4.5 Hz, 1 H, C-2 H), 4.74
(d, J = 11.7 Hz, 1 H, OCHPh), 4.64 (d, J = 6.6 Hz, 1 H, OCHO),
4.61 (d, J = 6.6 Hz, 1 H, OCH′O), 4.57 (d, J = 11.7 Hz, 1 H,
OCH′Ph), 4.09 (d, J = 2.0 Hz, 1 H, C-3 H), 3.72 (d, J = 10.2 Hz, 1
H, OCH), 3.70 (s, 2 H, OCH2), 3.62 (d, J = 10.2 Hz, 1 H, OCH′),
3.32 (s, 3 H, OCH3), 2.40–2.20 (br s, 1 H, OH), 1.55 (s, 3 H, CH3),
1.35 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 137.5, 128.4 (2 C), 127.8, 127.5 (2
C), 113.0, 105.0, 96.8, 89.1, 85.9, 83.8, 72.5, 67.4, 63.0, 55.4, 27.3,
26.8.
HRMS (ESI+): m/z [M + Na]+ calcd for C18H26NaO7: 377.15707;
found: 377.15645.
3-O-Benzyl-5-O-[tert-butyl(dimethyl)silyl]-4-(hydroxymethyl)-
1,2-O-(1-methylethylidene)-β-L-arabinofuranose (6)7b
A 37% aq solution of HCHO (40 mL) and 1 M aq NaOH (120 mL)
were added sequentially at 0 °C to a stirred solution of aldehyde 7a
(20.0 g, 71.94 mmol) in a mixture of H2O (100 mL) and THF (100
mL) at 0 °C, and the mixture was stirred at r.t. for 16 h. The solvent
(THF) was evaporated under reduced pressure and the residue was
extracted with EtOAc (3 × 250 mL). The organic layers were com-
bined, washed with brine (100 mL), dried (Na2SO4), and concentrat-
ed. The residue was purified by column chromatography (silica gel,
40% EtOAc–PE) to give 7b as a white solid; yield: 17.40 (78%);7a
mp 101–103 °C.
3-O-Benzyl-4-[(methoxymethoxy)methyl]-1,2-O-(1-methyleth-
ylidene)-β-L-arabino-pentodialdo-1,4-furanose (10)
DMSO (2.94 mL, 41.53 mmol) was added dropwise to a stirred so-
lution of oxalyl chloride (1.81 mL, 20.76 mmol) in CH2Cl2 (25 mL)
at –78 °C. After 20 min, a solution of 9 (4.90 g, 13.84 mmol) in
CH2Cl2 (15 mL) was added and the mixture was stirred at –78 °C
for 2 h. Et3N (11.55 mL, 83.05 mmol) was added and the mixture
was stirred and warmed to r.t. The mixture was then diluted with
CH2Cl2 (60 mL) and washed successively with H2O (40 mL) and
brine (40 mL) then dried (Na2SO4). Evaporation of the solvent at a
low temperature (10 °C) gave a pale-yellow solid; yield: 4.80
(98%); mp 78–80 °C; [α]D27 –203.1 (c 0.26, CHCl3).
TBSCl (8.27 g, 54.84 mmol) and imidazole (11.19 g, 164.52 mmol)
were added to a solution of compound 7b (17.0 g, 54.84 mmol) in
CH2Cl2 (255 mL) at –20 °C. The mixture was stirred for 1 h at
–20 °C and then warmed r.t.; CH2Cl2 (100 mL) was added, and the
mixture was washed successively with H2O (3 × 150 mL) and brine
(150 mL) then dried (Na2SO4), and concentrated. The residue was
purified by column chromatography (silica gel, 10% EtOAc–PE) to
give a white solid; yield: 13.49 (58%);7b mp 52–53 °C.
3-O-Benzyl-5-O-[tert-butyl(dimethyl)silyl]-4-[(methoxymeth-
oxy)methyl]-1,2-O-(1-methylethylidene)-β-L-arabinofuranose
(8)
IR (CHCl3): 3019, 2988, 2938, 1734, 1455, 1380, 1214, 1159, 1107,
1070, 1043, 1016, 917, 747, 667 cm–1.
1H NMR (300 MHz, CDCl3): δ = 9.80 (s, 1 H, CHO), 7.42–7.27 (m,
5 H, Ar-H), 6.07 (d, J = 3.6 Hz, 1 H, C-1 H), 4.71–4.52 (m, 5 H, C-
2 H, OCH2Ph, OCH2O), 4.30 (s, 1 H, C-3 H), 3.95 (d, J = 10.6 Hz,
1 H, OCH), 3.86 (d, J = 10.6 Hz, 1 H, OCH′), 3.29 (s, 3 H, OCH3),
1.43 (s, 3 H, CH3), 1.29 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 203.3, 136.8, 128.5 (2 C), 128.1,
127.6 (2 C), 112.0, 105.9, 96.6, 93.5, 84.6, 82.5, 72.9, 68.9, 55.3,
25.9, 25.5.
DIPEA (13.07 mL, 75.47 mmol), MOMCl (2.87 mL, 37.74 mmol),
and a catalytic amount of DMAP were added successively to a
stirred and cooled (0 °C) solution of alcohol 6 (8.0 g, 18.87 mmol)
in CH2Cl2 (40 mL) at 0 °C, and the mixture was stirred to r.t. for 8
h. H2O (40 mL) was added, and the mixture was extracted with
CH2Cl2 (2 ´ 50 mL). The organic layer was separated, washed with
brine (40 mL), dried (Na2SO4), and concentrated. The residue was
purified by column chromatography (silica gel, 7% EtOAc–PE) to
27
give a pale-yellow oil; yield: 8.12 (92%); [α]D –57.9 (c 0.16,
HRMS (ESI+): m/z [M + Na]+ calcd for C18H24NaO7: 375.14142;
CHCl3).
found: 375.14349.
IR (CHCl3): 2930, 2885, 2857, 1466, 1378, 1254, 1212, 1048, 838,
779, 749, 698 cm–1.
3-O-Benzyl-6,7-dideoxy-4-[(methoxymethoxy)methyl]-1,2-O-
(1-methylethylidene)-α-D-galacto-hept-6-enofuranose (5) and
3-O-Benzyl-6,7-dideoxy-4-[(methoxymethoxy)methyl]-1,2-O-
(1-methylethylidene)-β-L-altro-hept-6-enofuranose (ent-5)
A 1 M solution of CH2=CHMgBr in THF (4.26 mL, 4.26 mmol)
was added to a stirred solution of aldehyde 10 (0.50 g, 1.42 mmol)
in THF (5 mL) at 0 °C, and the mixture was stirred for 20 min. Sat.
aq NH4Cl (5 mL) was added, and the mixture was diluted with
EtOAc (20 mL), washed successively with H2O (20 mL) and brine
(20 mL), and dried (Na2SO4). The solvent was evaporated and the
residue was purified by column chromatography (silica gel, 15%
1H NMR (500 MHz, CDCl3): δ = 7.37–7.26 (m, 5 H, Ar-H), 5.98 (d,
J = 4.2 Hz, 1 H, C-1 H), 4.75–4.67 (m, 2 H, OCHPh, C-2 H), 4.65
(d, J = 6.3 Hz, 1 H, OCHO), 4.62 (d, J = 6.3 Hz, 1 H, OCH′O), 4.53
(d, J = 11.5 Hz, 1 H, OCH′Ph), 4.14 (br s, 1 H, C-3 H), 3.77 (d, J =
9.9 Hz, 1 H, OCH), 3.72 (d, J = 10.5 Hz, 1 H, OCH), 3.66 (d, J =
10.5 Hz, 1 H, OCH′), 3.63 (d, J = 9.9 Hz, 1 H, OCH′), 3.33 (s, 3 H,
OCH3), 1.55 (s, 3 H, CH3), 1.35 (s, 3 H, CH3), 0.86 [s, 9 H, (CH3)3],
0.03 (s, 3 H, CH3), 0.02 (s, 3 H, CH3).
Synthesis 2014, 46, 1532–1538
© Georg Thieme Verlag Stuttgart · New York

PAPER
6-O-Benzoylzeylenol
1535
EtOAc–PE) to give an inseparable mixture of allylic alcohols 5 and
ent-5 (1:5 ratio; 1H NMR) as a colorless oil; yield: 0.41 g (76%).
then filtered through a pad of Celite that was subsequently washed
with EtOAc. The solvent was evaporated, and the residue was puri-
fied by column chromatography (silica gel, 20% EtOAc–PE) to
give a colorless oil; yield: 2.06 (86%); [α]D27 –42.6 (c 0.21, CHCl3).
Ethyl (5E)-3-O-Benzyl-5,6-dideoxy-4-[(methoxymethoxy)meth-
yl]-1,2-O-(1-methylethylidene)-β-L-arabino-hept-5-enofuran-
uronate (11)
EtO2CCH2=PPh3 (5.25 g, 14.66 mmol) was added to a stirred solu-
tion of aldehyde 10 (4.30 g, 12.22 mmol) in CH2Cl2 at 0 °C, and the
mixture was stirred and warmed to r.t. over 2 h. The mixture was
concentrated and the residue was purified by column chromatogra-
phy (silica gel, 8% EtOAc–PE) to give a colorless oil; yield: 4.53
(88%); [α]D27 –82.7 (c 0.33, CHCl3).
IR (CHCl3): 3467, 2988, 2938, 2887, 1455, 1378, 1242, 1214, 1150,
1110, 1071, 1040, 1017, 909, 866, 750, 700, 667 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H, Ar-H), 5.95 (d,
J = 4.5 Hz, 1 H, C-1 H), 4.82–4.76 (m, 2 H, C-2 H, OCHPh), 4.65–
4.56 (m, 3 H, OCH′Ph, OCH2O), 4.17 (d, J = 2.5 Hz, 1 H, C-3 H),
3.92–3.86 (m, 1 H, CHOH), 3.74 (d, J = 10.0 Hz, 1 H, OCH), 3.66–
3.59 (m, 1 H, CH′OH), 3.51 (d, J = 10.0 Hz, 1 H, OCH′), 3.39–3.35
(m, 1 H, epoxy CH), 3.31 (s, 3 H, OCH3), 3.08–3.04 (d, J = 2.0 Hz,
1 H, epoxy CH′), 1.56 (s, 3 H, CH3), 1.40 (s, 3 H, CH3).
IR (CHCl3): 3019, 2984, 2936, 1718, 1454, 1372, 1304, 1266, 1214,
1111, 1075, 1043, 923, 746, 668 cm–1.
13C NMR (75 MHz, CDCl3): δ = 137.4, 128.3 (2 C), 127.8, 127.6 (2
C), 114.1, 104.6, 96.6, 86.9, 85.7, 84.3, 72.6, 68.0, 60.6, 56.2, 55.3,
55.2, 27.9, 27.8.
HRMS (ESI+): m/z [M + Na]+ calcd for C20H28NaO8: 419.16764;
found: 419.16508.
1H NMR (300 MHz, CDCl3): δ = 7.43–7.28 (m, 5 H, Ar-H), 7.0 (d,
J = 15.9 Hz, 1 H, olefinic), 6.17 (d, J = 15.9 Hz, 1 H, olefinic), 6.04
(d, J = 4.5 Hz, 1 H, C-1 H), 4.81–4.72 (m, 2 H, C-2 H, OCHPh),
4.65–4.53 (m, 3 H, OCH′Ph, OCH2O), 4.19 (q, J = 7.2 Hz, 2 H,
OCH2), 4.03 (d, J = 1.9 Hz, 1 H, C-3 H), 3.74 (d, J = 10.0 Hz, 1 H,
OCH), 3.57 (d, J = 10.0 Hz, 1 H, OCH′), 3.29 (s, 3 H, OCH3), 1.45
(s, 3 H, CH3), 1.36 (s, 3 H, CH3), 1.28 (t, J = 7.2 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 166.1, 146.6, 137.2, 128.4 (2 C),
127.9, 127.6 (2 C), 121.6, 113.4, 105.3, 96.6, 87.4, 87.3, 85.7, 72.6,
69.6, 60.5, 55.4, 27.1, 26.9, 14.2.
3-O-Benzyl-6,7-dideoxy-4-[(methoxymethoxy)methyl]-1,2-O-
(1-methylethylidene)-α-D-galacto-hept-6-enofuranose (5) from
13a
Ph3P (2.0 g, 7.65 mmol), imidazole (1.04 g, 15.30 mmol), and I2
(1.94 g, 7.65 mmol) were added sequentially to a solution of 13a
(2.02 g, 5.10 mmol) in anhydrous THF (20 mL) at 0 °C, and the
mixture as stirred for 20 min. The mixture was then washed with sat.
aq Na2S2O3 (30 mL) and extracted with EtOAc (50 mL). The ex-
tracts were washed with brine (30 mL) and concentrated to give the
iodo derivative 13b, which was used directly in the next reaction.
MS (ESI): m/z = 445 [M + Na]+.
(5E)-3-O-Benzyl-5,6-dideoxy-4-[(methoxymethoxy)methyl]-
1,2-O-(1-methylethylidene)-β-L-arabino-hept-5-enofuranose
(12)
A 25% solution of DIBAL-H in toluene (11.59 mL, 20.38 mmol)
was added to a stirred solution of 11 (4.30 g, 10.19 mmol) in anhy-
drous CH2Cl2 (22 mL) at 0 °C, and the mixture was stirred for 30
min. MeOH (25 mL) was added at 0 °C, and the mixture was stirred
for 10 min. Sat. aq sodium potassium tartrate (5 mL) was added and
the mixture was filtered through a pad of Celite that was then
washed with EtOAc (3 × 30 mL). The solvent was evaporated and
the residue was purified by column chromatography (silica gel,
Zn (1.33 g, 20.40 mmol) and NaI (0.77 g, 5.10 mmol) were added
to a solution of the iodide 13b (2.58 g, 5.10 mmol) in MeOH (20
mL), and the mixture was stirred at the reflux for 12 h. The solvent
was evaporated and the residue was purified by column chromatog-
raphy (silica gel, 15% EtOAc–PE) to give 5 as a colorless oil; yield:
1.67 (86%); [α]D27 +61.9 (c 0.37, CHCl3).
IR (CHCl3): 3473, 2988, 2937, 2884, 1455, 1376, 1241, 1214, 1149,
1109, 1068, 1016, 919, 864, 748, 699, 667 cm–1.
27
20% EtOAc–PE) to give a colorless oil; yield: 2.71 (70%); [α]D
–57.4 (c 0.25, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H, Ar-H), 6.0 (d,
J = 4.5 Hz, 1 H, C-1 H), 5.82 (ddd, J = 6.4, 10.6, 17.0 Hz, 1 H, ole-
finic), 5.28 (d, J = 17.0 Hz, 1 H, olefinic), 5.18 (d, J = 10.6 Hz, 1 H,
olefinic), 4.83 (dd, J = 3.0, 4.5 Hz, 1 H, C-2 H), 4.76 (d, J = 11.7
Hz, 1 H, OCHPh), 4.60 (d, J = 6.8 Hz, 1 H, OCHO), 4.58 (d, J = 6.8
Hz, 1 H, OCH′O), 4.54 (d, J = 11.5 Hz, 1 H, OCH′Ph), 4.15 (d, J =
6.4 Hz, 1 H, CHOH), 4.12 (d, J = 3.0 Hz, 1 H, C-3 H), 3.69 (d, J =
10.6 Hz, 1 H, OCH), 3.59 (d, J = 10.6 Hz, 1 H, OCH′), 3.29 (s, 3 H,
OCH3), 2.60 (d, J = 6.8 Hz, 1 H, OH), 1.57 (s, 3 H, CH3), 1.39 (s, 3
H, CH3).
13C NMR (75 MHz, CDCl3): δ = 137.4, 135.2, 128.3 (2 C), 127.8,
127.7 (2 C), 117.4, 113.9, 104.8, 96.7, 89.7, 86.9, 85.0, 75.2, 72.3,
67.7, 55.3, 27.9, 27.7.
HRMS (ESI+): m/z [M + Na]+ calcd for C20H28NaO7: 403.17272;
found: 403.17178.
IR (CHCl3): 3423, 2929, 1454, 1377, 1213, 1105, 1028, 918, 867,
750, 700, 667 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H, Ar-H), 6.03 (d,
J = 4.5 Hz, 1 H, C-1 H), 5.97 (dt, J = 4.9, 15.9 Hz, 1 H, olefinic),
5.82 (d, J = 15.9 Hz, 1 H, olefinic), 4.80 (dd, J = 2.6, 4.5 Hz, 1 H,
C-2 H), 4.78 (d, J = 11.7 Hz, 1 H, OCHPh), 4.64–4.53 (m, 3 H,
OCH′Ph, OCH2O), 4.17–4.09 (m, 2 H, allylic OCH2), 4.01 (d, J =
2.6 Hz, 1 H, C-3 H), 3.73 (d, J = 10.2 Hz, 1 H, OCH), 3.47 (d, J =
10.2 Hz, 1 H, OCH′), 3.30 (s, 3 H, OCH3), 1.49 (s, 3 H, CH3), 1.39
(s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 137.5, 130.1, 129.8, 128.3 (2 C),
127.8, 127.6 (2 C), 113.4, 104.9, 96.6, 88.4, 86.9, 86.6, 72.4, 70.4,
62.8, 55.3, 27.6, 27.4.
HRMS (ESI+): m/z [M + Na]+ calcd for C20H28NaO7: 403.17272;
found: 403.17151.
5,6-Anhydro-3-O-benzyl-4-[(methoxymethoxy)methyl]-1,2-O-
(1-methylethylidene)-D-glycero-β-L-altro-heptofuranose (14a)
Ti(i-PrO)4 (0.03 g, 0.10 mmol) was added to a solution of (–)-DIPT
(0.05 g, 0.02 mmol) in anhydrous CH2Cl2 (2 mL) containing pow-
dered 4 Å MS at –20 °C and the mixture was stirred for 20 min.
Cumene hydroperoxide (0.30 g, 1.95 mmol) was added dropwise
and the mixture was stirred for an additional 20 min. A solution of
allylic alcohol 12 (0.37 g, 0.97 mmol) in anhydrous CH2Cl2 (1 mL)
was added, and the mixture was stirred at –20 °C for 20 min, then
kept at –20 °C for 14 h. Workup as described for 13a and purifica-
tion of the residue by column chromatography (silica gel, 20%
EtOAc–PE) gave a colorless oil; yield: 0.35 (90%); [α]D27 +40.0 (c
0.10, CHCl3).
5,6-Anhydro-3-O-benzyl-4-[(methoxymethoxy)methyl]-1,2-O-
(1-methylethylidene)-L-glycero-α-D-galacto-heptofuranose
(13a)
Ti(i-PrO)4 (0.17 g, 0.61 mmol) was added to a solution of (+)-DIPT
(0.28 g, 1.21 mmol) in anhydrous CH2Cl2 (10 mL) containing pow-
dered 4 Å MS at –20 °C, and the mixture was stirred for 20 min.
Cumene hydroperoxide (1.86 mL, 12.11 mmol) was added drop-
wise, and the mixture was stirred for 20 min. A solution of allylic
alcohol 12 (2.30 g, 6.05 mmol) in anhydrous CH2Cl2 (7 mL) was
then added and the mixture was stirred at –20 °C for 140 min, then
kept at –20 °C for 14 h. The reaction was quenched with 10%
NaOH in brine (11.5 mL) and the mixture was stirred for 3 h. It was
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1532–1538

1536
P. S. Reddy, G. V. M. Sharma
PAPER
IR (CHCl3): 3481, 2988, 2938, 2886, 1455, 1379, 1243, 1213, 1152,
1110, 1019, 916, 867, 814, 753, 700, 667 cm–1.
4.08 (d, J = 7.9 Hz, 1 H, allylic OCH), 3.74 (d, J = 10.2 Hz, 1 H,
OCH), 3.58 (d, J = 10.2 Hz, 1 H, OCH′), 3.34 (s, 3 H, OCH3), 3.26
(s, 3 H, OCH3), 1.61 (s, 3 H, CH3), 1.41 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 137.7, 133.4, 128.2 (2 C), 127.7 (2
C), 127.6, 119.9, 113.9, 104.9, 96.6, 93.8, 88.7, 87.3, 85.2, 78.6,
72.2, 68.0, 55.6, 55.2, 28.1, 27.8.
1H NMR (300 MHz, CDCl3): δ = 7.44–7.30 (m, 5 H, Ar-H), 6.0 (d,
J = 4.7 Hz, 1 H, C-1 H), 4.82 (dd, J = 3.2, 4.7 Hz, 1 H, C-2 H), 4.77
(d, J = 11.5 Hz, 1 H, OCHPh), 4.62 (dd, J = 6.4, 8.3 Hz, 2 H,
OCH2O), 4.52 (d, J = 11.5 Hz, 1 H, OCH′Ph), 3.95 (d, J = 3.2 Hz,
1 H, C-3 H), 3.91–3.80 (m, 1 H, CHOH), 3.75 (d, J = 10.2 Hz, 1 H,
OCH), 3.65–3.55 (m, 1 H, CH′OH), 3.54 (d, J = 10.2 Hz, 1 H,
OCH′), 3.31 (s, 3 H, OCH3), 3.22 (d, J = 2.7 Hz, 1 H, epoxy CH),
3.03–2.98 (m, 1 H, epoxy CH′), 1.57 (s, 3 H, CH3), 1.42 (s, 3 H,
CH3).
13C NMR (75 MHz, CDCl3): δ = 137.1, 128.2 (2 C), 127.7, 127.6 (2
C), 113.7, 104.5, 96.5, 86.9, 85.7, 83.1, 72.0, 68.0, 60.8, 55.1, 55.0
(2 C), 27.7 (2 C).
HRMS (ESI+): m/z [M + Na]+ calcd for C20H28NaO8: 419.16764;
found: 419.16601.
HRMS (ESI+): m/z [M + Na]+ calcd for C22H32NaO8: 447.19894;
found: 447.19805.
4-O-Benzyl-1,2-dideoxy-5-C-[(1R)-1-(methoxymethoxy)prop-2-
en-1-yl]-6-O-(methoxymethyl)-D-xylo-hex-1-enitol (4)
A solution of furanose 15 (1.20 g, 2.83 mmol) in 70% aq AcOH (12
mL) was stirred at 55 °C for 8 h. The mixture was neutralized with
solid NaHCO3 and then extracted with EtOAc (3 × 40 mL). The or-
ganic layer was dried (Na2SO4) and concentrated to give a residue
that was purified by column chromatography (silica gel, 40%
EtOAc–PE) to give 16 [yield: 0.69 g (63%)] as a colorless oil, along
with trace amounts of triol 17.
3-O-Benzyl-6,7-dideoxy-4-[(methoxymethoxy)methyl]-1,2-O-
(1-methylethylidene)-β-L-altro-hept-6-enofuranose (ent-5) from
14a
Ph3P (0.30 g, 1.14 mmol), imidazole (0.15 g, 2.27 mmol), and I2
(0.29 g, 1.14 mmol) were added sequentially to a solution of 14a
(0.30 g, 0.76 mmol) in anhydrous THF (5 mL) at 0 °C, and the mix-
ture was stirred for 20 min. Workup as described for 13b gave io-
dide 14b, which was used directly in the next reaction.
A suspension of Ph3P+MeBr– (2.23 g, 6.25 mmol) in anhydrous
THF (4 mL) at 0 °C was treated with a 2.5 M solution of n-BuLi in
hexane (2.09 mL, 5.21 mmol), and the mixture was stirred for 25
min. A solution of 16 (0.40 g, 1.04 mmol) in anhydrous THF (3 mL)
was added, and the resulting mixture was stirred while it warmed to
r.t. for 2 h. The mixture was then diluted with ice-cold H2O (15 mL)
and extracted with EtOAc (2 × 20 mL). The organic phases were
combined, washed with brine (10 mL), and dried (Na2SO4). The sol-
vent was evaporated under reduced pressure and the residue was pu-
rified by column chromatography (silica gel, 30% EtOAc–PE) to
To a solution of 14b (0.38 g, 0.76 mmol) in MeOH (6 mL), Zn (0.20
g, 3.03 mmol) and NaI (0.11 g, 1.14 mmol) were added and the mix-
ture was stirred at the reflux for 10 h. The solvent was evaporated
and the residue was purified by column chromatography (silica gel,
15% EtOAc–PE) to give ent-5a as a colorless oil; yield: 0.21 (72%);
[α]D27 +33.8 (c 0.25, CHCl3).
27
give 4 as a colorless oil; yield: 0.26 (65%); [α]D –86.4 (c 0.40,
CHCl3).
IR (CHCl3): 3546, 3395, 3017, 2932, 2892, 1451, 1404, 1215, 1149,
1105, 1026, 920, 746, 667 cm–1.
IR (CHCl3): 3481, 2987, 2935, 2886, 1455, 1376, 1214, 1151, 1108,
1074, 1039, 922, 865, 749, 700, 667 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.36–7.27 (m, 5 H, Ar-H), 6.12–
5.87 (m, 2 H, olefinic), 5.45–5.27 (m, 3 H, olefinic), 5.19 (ddd, J =
1.5, 3.2, 10.6 Hz, 1 H, olefinic), 4.78–4.58 (m, 7 H, OCH2Ph, 2 ×
OCH2O, allylic CH), 4.21 (d, J = 8.1 Hz, 1 H, allylic CH′), 3.84 (d,
J = 1.5 Hz, 1 H, CHOBn), 3.83 (d, J = 10.2 Hz, 1 H, OCH), 3.63 (d,
J = 10.2 Hz, 1 H, OCH′), 3.39 (s, 3 H, OCH3), 3.36 (s, 3 H, OCH3).
13C NMR (75 MHz, CDCl3): δ = 139.8, 138.2, 133.7, 128.2 (2 C),
127.6 (3 C), 120.2, 114.7, 97.2, 94.3, 81.4, 80.2, 77.3, 75.0, 70.9,
68.9, 56.1, 55.7.
1H NMR (500 MHz, CDCl3): δ = 7.39–7.27 (m, 5 H, Ar-H), 5.96 (d,
J = 4.3 Hz, 1 H, C-1 H), 5.81 (ddd, J = 6.2, 10.5, 16.8 Hz, 1 H, ole-
finic), 5.39 (d, J = 16.8 Hz, 1 H, olefinic), 5.21 (d, J = 10.5 Hz, 1 H,
olefinic), 4.83–4.78 (m, 1 H, C-2 H), 4.71 (d, J = 11.5 Hz, 1 H,
OCHPh), 4.60 (d, J = 6.2 Hz, 1 H, OCHO), 4.57 (d, J = 6.2 Hz, 1 H,
OCH′O), 4.53 (d, J = 11.5 Hz, 1 H, OCH′Ph), 4.30–4.25 (m, 2 H, C-
3 H, CHOH), 3.75 (d, J = 10.5 Hz, 1 H, OCH), 3.51 (d, J = 10.5 Hz,
1 H, OCH′), 3.29 (s, 3 H, OCH3), 2.83 (d, J = 2.4 Hz, 1 H, OH), 1.58
(s, 3 H, CH3), 1.37 (s, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 137.5, 134.6, 128.3 (2 C), 127.7,
127.6 (2 C), 117.6, 113.7, 104.6, 96.7, 90.6, 87.0, 82.8, 73.0, 72.1,
68.1, 55.4, 27.9, 27.6.
HRMS (ESI+): m/z [M + Na]+ calcd for C20H28NaO7: 403.17272;
found: 403.17189.
HRMS (ESI+): m/z [M + Na]+ calcd for C20H30NaO7: 405.18837;
found: 405.18718.
(1S,2R,3S,6R)-2-(Benzyloxy)-6-(methoxymethoxy)-1-[(meth-
oxymethoxy)methyl]cyclohex-4-ene-1,3-diol (18)
Grubbs II catalyst (10 mol%) was added to a solution of hexenitol 4
(0.20 g, 0.52 mmol) in anhydrous toluene (32 mL), and the mixture
was stirred at r.t. under N2 for 2 h. The mixture was then evaporated
to dryness to give a brown residue that was purified by column chro-
matography (silica gel, 35% EtOAc–PE) to give a colorless oil;
yield: 0.14 (76%); [α]D27 –3.6 (c 0.25, CHCl3).
3-O-Benzyl-6,7-dideoxy-4-[(methoxymethoxy)methyl]-5-O-
(methoxymethyl)-1,2-O-(1-methylethylidene)-α-D-galacto-hept-
6-enofuranose (15)
DIPEA (2.73 mL, 15.79 mmol) MOMCl (0.60 mL, 7.89 mmol), and
a catalytic amount of DMAP were added sequentially to a stirred
and cooled (0 °C) solution of 5 (1.50 g, 3.95 mmol) in CH2Cl2 (8
mL) at 0 °C, and the mixture was warmed to r.t. with stirring for 12
h. Workup as described for 8 and purification of the residue by col-
umn chromatography (silica gel, 15% EtOAc–PE) gave a pale-
yellow oil; yield: 1.31 (78%); [α]D27 –39.7 (c 0.48, CHCl3).
IR (CHCl3): 3436, 3032, 2927, 2889, 2852, 2825, 1453, 1400, 1215,
1146, 1096, 1029, 958, 915, 772, 746, 700, 668 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.42–7.29 (m, 5 H, Ar-H), 5.84 (d,
J = 11.7 Hz, 1 H, olefinic), 5.80 (d, J = 11.7 Hz, 1 H, olefinic), 4.84–
4.61 (m, 6 H, OCH2Ph, 2 × OCH2O), 4.47 (d, J = 6.0 Hz, 1 H, allylic
CH), 4.08 (s, 1 H, allylic CH′), 3.93 (d, J = 10.6 Hz, 1 H, OCH), 3.85
(d, J = 10.6 Hz, 1 H, OCH), 3.67 (d, J = 6.0 Hz, 1 H, CHOBn), 3.39
(s, 6 H, 2 × OCH3), 3.15–3.00 (br s, 1 H, OH).
IR (CHCl3): 3016, 2988, 2938, 2888, 1455, 1379, 1240, 1214, 1147,
1075, 1024, 918, 865, 748, 699, 667 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.40–7.27 (m, 5 H, Ar-H), 6.02 (d,
J = 4.5 Hz, 1 H, C-1 H), 5.72 (ddd, J = 7.9, 10.6, 17.0 Hz, 1 H, ole-
finic), 5.29 (d, J = 10.6 Hz, 1 H, olefinic), 5.27 (d, J = 17.0 Hz, 1 H,
olefinic), 4.84 (dd, J = 3.4, 4.5 Hz, 1 H, C-2 H), 4.76 (d, J = 11.3
Hz, 1 H, OCHPh), 4.68 (d, J = 6.8 Hz, 1 H, OCHO), 4.62–4.50 (m,
4 H, OCH′Ph, OCH′O, OCH2O), 4.17 (d, J = 3.4 Hz, 1 H, C-3 H),
13C NMR (75 MHz, CDCl3): δ = 138.1, 130.9, 128.5 (2 C), 128.0 (2
C), 127.9, 127.0, 97.6, 97.0, 81.6, 75.6 (2 C), 74.6, 70.6, 69.7, 55.7,
55.5.
HRMS (ESI+): m/z [M + Na]+ calcd for C18H26NaO7: 377.15707;
found: 377.15648.
Synthesis 2014, 46, 1532–1538
© Georg Thieme Verlag Stuttgart · New York

PAPER
6-O-Benzoylzeylenol
1537
(1S,4R,5S,6R)-6-(Benzyloxy)-5-hydroxy-4-(methoxymethoxy)-
5-[(methoxymethoxy)methyl]cyclohex-2-en-1-yl Benzoate (19)
BzCl (0.07 mL, 0.56 mmol) was added to a stirred solution of diol
18 (0.10 g, 0.28 mmol) and pyridine (0.09 mL, 1.13 mmol) in
CH2Cl2 (2 mL), and the mixture was stirred at r.t. for 8 h. The reac-
tion was quenched with MeOH (0.3 mL), and the mixture was
stirred for 15 min. H2O (10 mL) was added and the aqueous phase
was extracted with CH2Cl2 (3 × 5 mL). The organic layers were
combined, washed sequentially with 1.0 M aq NaOH (2 × 5 mL)
and brine (5 mL), dried (NaSO4), and concentrated. The residue was
purified by column chromatography (silica gel, 15% EtOAc–PE) to
IR (CHCl3): 3592, 3020, 2927, 1719, 1452, 1316, 1262, 1214, 1095,
1069, 1026, 749, 667 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.03 (dd, J = 1.5, 8.5 Hz, 2 H, Ar-
H), 7.89 (dd, J = 1.3, 8.5 Hz, 2 H, Ar-H), 7.67 (dd, J = 1.3, 8.5 Hz,
2 H, Ar-H), 7.62–7.55 (m, 1 H, Ar-H), 7.50–7.21 (m, 13 H, Ar-H),
6.09–5.85 (m, 4 H, olefinic, 2 × CHOBz), 5.02 (d, J = 11.5 Hz, 1 H,
CHOBz), 4.85 (d, J = 11.5 Hz, 1 H, CH′OBz), 4.77 (d, J = 12.1 Hz,
1 H, OCHPh), 4.58 (d, J = 12.1 Hz, 1 H, OCH′Ph), 4.35 (d, J = 3.6
Hz, 1 H, CHOBn), 2.92–2.86 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): δ = 166.3, 165.8, 165.7, 137.1, 133.4,
133.2, 132.8, 129.7 (2 C), 129.6, 129.5 (3 C), 129.3 (2 C), 129.2,
129.1, 128.6 (2 C), 128.5 (4 C), 128.3 (3 C), 128.0 (2 C), 126.6,
76.7, 74.0, 73.5, 72.6, 70.2, 65.3.
27
give a colorless oil; yield: 0.11 (85%); [α]D +239.9 (c 0.22,
CHCl3).
IR (CHCl3): 3486, 3432, 3032, 2929, 2889, 2852, 2824, 1715, 1602,
1452, 1397, 1316, 1263, 1214, 1147, 1097, 1038, 956, 916, 771,
749, 712, 667 cm–1.
HRMS (ESI+): m/z [M + Na]+ calcd for C35H30NaO8: 601.18329;
found: 601.18451.
1H NMR (300 MHz, CDCl3): δ = 8.05 (d, J = 7.2 Hz, 2 H, Ar-H),
7.57 (dd, J = 7.2, 7.6 Hz, 1 H, Ar-H), 7.44 (t, J = 7.6 Hz, 2 H, Ar-
H), 7.34–7.19 (m, 5 H, Ar-H), 6.01–5.92 (m, 1 H, CHOBz), 5.90–
5.82 (m, 2 H, olefinic), 4.87 (d, J = 6.4 Hz, 1 H, OCHO), 4.85 (d,
J = 11.7 Hz, 1 H, OCHPh), 4.72 (d, J = 6.4 Hz, 1 H, OCH′O), 4.69
(d, J = 11.7 Hz, 1 H, OCH′Ph), 4.59 (d, J = 6.4 Hz, 1 H, OCHO),
4.55 (d, J = 6.4 Hz, 1 H, OCH′O), 4.22 (d, J = 3.0 Hz, 1 H, allylic
CH), 4.09 (d, J = 5.3 Hz, 1 H, CHOBn), 3.96 (d, J = 11.0 Hz, 1 H,
OCH), 3.83 (d, J = 11.0 Hz, 1 H, OCH′), 3.42 (s, 3 H, OCH3), 3.30
(s, 3 H, OCH3), 3.14–3.06 (br s, 1 H, OH).
(1S,4R,5R,6R)-5-(Benzoyloxymethyl)-5,6-dihydroxy cyclohex-
2-ene-1,4-diyl Dibenzoate (2; 6-O-Benzoylzeylenol)
TiCl4 (0.02 g, 0.09 mmol) in CH2Cl2 (1 mL) was added to a solution
of tribenzoate 21 (0.03 g, 0.04 mmol) in CH2Cl2 (1.5 mL) at 0 °C
under N2, and the mixture was stirred at r.t. for 3 h. Sat. aq NaHCO3
(5 mL) was added and the mixture was extracted with CHCl3 (2 ×
15 mL). The organic layers were combined, washed successively
with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and concentrat-
ed under reduced pressure. The residue was purified by column
chromatography (silica gel, 30% EtOAc–PE) to give a white solid;
27
13C NMR (75 MHz, CDCl3): δ = 165.9, 137.8, 133.0, 130.1, 130.0,
129.6 (2 C), 128.3 (4 C), 127.9 (2 C), 127.7, 126.4, 97.6, 97.0, 78.0,
75.6, 75.5, 74.3, 72.1, 69.8, 55.6, 55.5.
yield: 0.02 (71%); mp 137–139 °C; [α]D –58.1 (c 0.12, CHCl3)
{lit.1b [a]22D –59.7 (c 0.39, CHCl3)}.
IR (CHCl3): 3485, 2924, 2853, 1720, 1452, 1318, 1267, 1217, 1111,
1070, 1027, 964, 772, 710, 668 cm–1.
HRMS (ESI+): m/z [M + Na]+ calcd for C25H30NaO8: 481.18329;
1H NMR (500 MHz, CDCl3): δ = 8.05 (d, J = 7.7 Hz, 2 H, Ar-H),
8.03 (d, J = 8.3 Hz, 2 H, Ar-H), 7.86 (d, J = 7.7 Hz, 2 H, Ar-H),
7.61–7.53 (m, 2 H, Ar-H), 7.50 (dd, J = 7.2, 7.7 Hz, 1 H, Ar-H),
7.47–7.37 (m, 4 H, Ar-H), 7.33 (t, J = 7.7 Hz, 2 H, Ar-H), 6.09 (dd,
J = 2.8, 9.9 Hz, 1 H, CHOBz), 6.02 (dd, J = 1.7, 9.9 Hz, 1 H,
CH′OBz), 5.84–5.76 (m, 2 H, olefinic), 4.92 (d, J = 12.1 Hz, 1 H,
CHOBz), 4.63 (d, J = 12.1 Hz, 1 H, CH′OBz), 4.35 (d, J = 5.0 Hz,
1 H, OCH), 3.64–3.57 (br s, 1 H, OH), 3.36–3.27 (br s, 1 H, OH).
13C NMR (75 MHz, CDCl3): δ = 167.1, 167.0, 165.7, 133.42,
133.39, 133.1, 129.8 (2 C), 129.7 (2 C), 129.6 (2 C), 129.4, 129.3,
129.2, 128.7, 128.5 (2C), 128.4 (2 C), 128.3 (2 C), 126.6, 74.9, 73.4,
71.6, 71.3, 66.7.
found: 481.18353.
(1S,4R,5S,6R)-6-(Benzyloxy)-4,5-dihydroxy-5-(hydroxymeth-
yl)cyclohex-2-en-1-yl Benzoate (20)
A solution of 19 (0.10 g, 0.22 mmol) and TFA (0.2 mL) in CH2Cl2
(2 mL) was stirred at 0 °C to r.t. for 2 h. The reaction was then
quenched with DIPEA and H2O (5 mL) was added. The mixture was
extracted with CH2Cl2 (2 × 10 mL), and the organic layers were
combined, washed with brine (5 mL), dried (Na2SO4), and concen-
trated. The residue was purified by column chromatography (silica
gel, 60% EtOAc–PE) to give a pale-yellow syrup; yield: 0.055
(70%); [α]D27 +238.0 (c 0.15, CHCl3).
IR (CHCl3): 3430, 3020, 2925, 2854, 1713, 1451, 1317, 1214, 1109,
1027, 746, 667 cm–1.
HRMS (ESI+): m/z [M + Na]+ calcd for C28H24NaO8: 511.13634;
found: 511.13675.
1H NMR (300 MHz, CDCl3): δ = 8.05 (d, J = 7.4 Hz, 2 H, Ar-H),
7.59 (dd, J = 7.3, 7.5 Hz, 1 H, Ar-H), 7.46 (dd, J = 7.7, 7.6 Hz, 2 H,
Ar-H), 7.33–7.21 (m, 5 H, Ar-H), 5.96 (dd, J = 2.9, 8.7 Hz, 1 H,
CHOBz), 5.87–5.77 (m, 2 H, olefinic), 4.85 (d, J = 11.2 Hz, 1 H,
OCHPh), 4.68 (d, J = 11.2 Hz, 1 H, OCH′Ph), 4.38 (d, J = 2.6 Hz,
1 H, allylic CH), 4.06 (d, J = 5.6 Hz, 1 H, CHOBn), 3.94 (d, J = 11.8
Hz, 1 H, OCH), 3.83 (d, J = 11.8 Hz, 1 H, OCH′), 3.12–2.45 (br s,
1 H, OH).
Acknowledgment
The authors are grateful to the Council of Scientific and Industrial
Research, New Delhi, India for the financial support (ORIGIN).
P.S.R. thanks the University Grants Commission (UGC), New
Delhi, India, for the award of a research fellowship.
13C NMR (75 MHz, CDCl3): δ = 165.9, 137.4, 133.3, 130.7, 129.8,
129.7 (2 C), 128.5 (4 C), 128.1 (3 C), 126.5, 78.4, 75.0, 74.2, 72.2,
71.4, 65.0.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
HRMS (ESI+): m/z [M + Na]+ calcd for C21H22NaO6: 393.13086;
found: 393.13151.
References
(1S,4R,5S,6R)-5-[(Benzoyloxy)methyl]-6-(benzyloxy)-5-hy-
droxycyclohex-2-ene-1,4-diyl Dibenzoate (21)
(1) (a) Tuntiwachwuttikul, P.; Pancharoen, O.; Bubb, W. A.;
Hambly, T. W.; Taylor, W. C.; Reutrakul, V. Aust. J. Chem.
1987, 40, 2049. (b) Pancharoen, O.; Tuntiwachwuttikul, P.;
Taylor, W. C. Phytochemistry 1989, 28, 1143. (c) Tang, S.
W.; Sukari, M. A.; Rahmani, M.; Lajis, N. H.; Ali, A. M.
Molecules 2011, 16, 3018.
BzCl (0.04 mL, 0.32 mmol) was added to a stirred solution of diol
20 (0.03 g, 0.08 mmol) and pyridine (0.04 mL, 0.49 mmol) in
CH2Cl2 (1 mL), and the mixture was stirred at r.t. for 8 h. Workup
as described for 19 and purification of the residue by column chro-
matography (silica gel, 20% EtOAc–PE) gave a colorless oil; yield:
0.04 (81%); [α]D27 –22.6 (c 0.13, CHCl3).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1532–1538

1538
P. S. Reddy, G. V. M. Sharma
PAPER
(2) (a) Pan, X.-P.; Qin, Y.-P.; Chen, R.-Y.; Yu, D.-Q. Acta
Pharmacol. Sin. 1998, 33, 275. (b) Tudla, F. A.; Aguinaldo,
A. M.; Krohn, K.; Hussain, H.; Macabeo, A. P. G. Biochem.
Syst. Ecol. 2007, 35, 45.
(3) Taneja, S. C.; Koul, S. K.; Pushpangadan, P.; Dhar, K. L.;
Daniewski, W. M.; Schilf, W. Phytochemistry 1991, 30, 871.
(4) (a) Xu, Q.-M.; Zou, Z.-M.; Xu, L.-Z.; Yang, S.-L. Chem.
Pharm. Bull. 2005, 53, 826. (b) Zhang, C.-R.; Yang, S.-P.;
Liao, S.-G.; Wu, Y.; Yue, J.-M. Helv. Chim. Acta 2006, 89,
1408. (c) Xu, Q.-M.; Liu, Y.-L. Zhongcaoyao 2007, 38,
1654. (d) Zhang, C.-R.; Wu, Y.; Yue, J.-M. Zhongguo
Tianran Yaowu 2010, 8, 84.
(5) Note that in ref. 4b, the zeylenol isolated from Uvaria rufa is
depicted as the (–)-1 enantiomer, although no chiroptical
data are presented. A subsequent report on this same species
assigned the isolate as (+)-1 on the basis of its positive [α]D
value; see ref. 2b.
(6) Palframan, M. J.; Kociok-Köhn, G.; Lewis, S. E. Chem. Eur.
J. 2012, 18, 4766.
(7) (a) Youssefyeh, R. D.; Verheyden, J. P. H.; Moffatt, J. G.
J. Org. Chem. 1979, 44, 1301. (b) Maity, J. K.; Ghosh, R.;
Drew, M. G. B.; Achari, B.; Mandal, S. B. J. Org. Chem.
2008, 73, 4305. (c) Sharma, G. V. M.; Reddy, P. S.;
Chatterjee, D.; Kunwar, A. C. J. Org. Chem. 2011, 76, 1562.
(8) (a) Li, Y.-L.; Wu, Y.-L. Liebigs Ann. 1996, 2079. (b) Rao, J.
P.; Rao, B. V. Tetrahedron: Asymmetry 2010, 21, 930.
(9) (a) Totokotsopoulos, S. M.; Koumbis, A. E.; Gallos, J. K.
Tetrahedron 2008, 64, 3998. (b) Lo, H.-J.; Chen, C.-Y.;
Zheng, W.-L.; Yeh, S.-M.; Yan, T.-H. Eur. J. Org. Chem.
2012, 2780.
(10) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
(b) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953. (c) Hassan, H. M. A. Chem. Commun. 2010,
46, 9100.
Synthesis 2014, 46, 1532–1538
© Georg Thieme Verlag Stuttgart · New York